The midfacial segment pain: little known disorder in need of scientific evaluation.

Despite its inclusion in the International Classification of Orofacial Pain, tension-type orofacial pain has little support in the scientific literature. However, a similar-in-phenotype orofacial pain perceived in the middle segment of the face has been described by few case series from mostly ear, nose and throat clinics. The authors of these descriptions used the term 'midfacial segment pain'. Patients had no significant sinonasal disorder in these studies, but experienced symmetrical pain perceived mostly over the maxillary and ethmoid sinuses. No aura or autonomic symptoms were present apart from mild nasal congestion or rhinorrhoea in some individuals. This description appears similar to tension-type headache, but with midfacial location. In this viewpoint, we indicate a need to fill this gap in scientific knowledge and propose a multicentre interdisciplinary study that would give a detailed description of this type of orofacial pain.

Expression and Regulatory Mechanisms of MicroRNA in Cholesteatoma: A Systematic Review.

Cholesteatoma is a temporal bone disease characterized by dysfunctions of keratinocytes. MicroRNAs (miRNAs) are evolutionary conserved noncoding RNAs that regulate mRNA expression. They can be packaged into exosomes and transported to target cells that can be used in the future therapy of cholesteatoma. This study aimed to collect knowledge on the role of miRNAs and exosomal miRNAs in cholesteatoma and was conducted according to the PRISMA guidelines for systematic reviews. Four databases were screened: Pubmed/MEDLINE, Web of Science, Scopus, and the Cochrane Library. The last search was run on the 6th of June 2023. We included full-text original studies written in English, which examined miRNAs in cholesteatoma. The risk of bias was assessed using the Office of Health Assessment and Translation (OHAT) Risk of Bias Rating Tool, modified for the needs of this review. We identified 118 records and included 18 articles. Analyses revealed the downregulation of exosomal miR-17 as well as miR-10a-5p, miR-125b, miR-142-5p, miR34a, miR-203a, and miR-152-5p and the overexpression of exosomal miR-106b-5p as well as miR-1297, miR-26a-5p, miR-199a, miR-508-3p, miR-21-3p, miR-584-5p, and miR-16-1-3p in cholesteatoma. The role of differentially expressed miRNAs in cholesteatoma, including cell proliferation, apoptosis, the cell cycle, differentiation, bone resorption, and the remodeling process, was confirmed, making them a potential therapeutic target in this disease.

Roles of Exosomes in Chronic Rhinosinusitis: A Systematic Review.

The pathophysiology of chronic rhinosinusitis (CRS) is multifactorial and not entirely clear. The objective of the review was to examine the current state of knowledge concerning the role of exosomes in CRS. For this systematic review, we searched PubMed/MEDLINE, Scopus, CENTRAL, and Web of Science databases for studies published until 7 August 2022. Only original research articles describing studies published in English were included. Reviews, book chapters, case studies, conference papers, and opinions were excluded. The quality of the evidence was assessed with the modified Office and Health Assessment and Translation (OHAT) Risk of Bias Rating Tool for Human and Animal Studies. Of 250 records identified, 17 were eligible, all of which had a low to moderate risk of overall bias. Presented findings indicate that exosomal biomarkers, including proteins and microRNA, act as promising biomarkers in the diagnostics and prognosis of CRS patients and, in addition, may contribute to finding novel therapeutic targets. Exosomes reflecting tissue proteomes are excellent, highly available material for studying proteomic alterations noninvasively. The first steps have already been taken, but more advanced research on nasal exosomes is needed, which might open a wider door for individualized medicine in CRS.

Application of Extracellular Vesicles in Allergic Rhinitis: A Systematic Review.

The pathophysiology of allergic rhinitis (AR), one of the most common diseases in the world, is still not sufficiently understood. Extracellular vesicles (EVs), which are secreted by host and bacteria cells and take part in near and distant intracellular communication, can provide information about AR. Recently, attention has been drawn to the potential use of EVs as biomarkers, vaccines, or transporters for drug delivery. In this review, we present an up-to-date literature overview on EVs in AR to reveal their potential clinical significance in this condition. A comprehensive and systematic literature search was conducted following PRISMA statement guidelines for original, completed articles, available in English concerning EVs and AR. For this purpose, PubMed/MEDLINE, Scopus, Web of Science, and Cochrane, were searched up until 10 Novenmber 2022. From 275 records, 18 articles were included for analysis. The risk of bias was assessed for all studies as low or moderate risk of overall bias using the Office and Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal Studies. We presented the role of exosomes in the pathophysiology of AR and highlighted the possibility of using exosomes as biomarkers and treatment in this disease.

Non-classical presentation of congenital cholesteatoma as cerebrospinal fluid rhinorrhea - Case report and systematic review of the literature.

OBJECTIVE: Congenital cholesteatoma (CC) becomes clinically apparent as a cholesteatoma usually during childhood. Nontraumatic otogenic cerebrospinal fluid (CSF) rhinorrhea with an intact tympanic membrane is a very rare symptom. METHODS: The review of recent literature and case report of the 60-year old patient - a trumpeter presented with nontraumatic otogenic CSF rhinorrhea, intact tympanic membrane on microotoscopy, and besides colorless fluid in right nasal cavity, normal finding on nasal endoscopy examination. RESULTS: CSF rhinorrhea was caused by CC in the petrous bone apex. Early diagnosis was facilitated by computed tomography scanning. Complete cholesteatoma removal was accomplished using a middle fossa craniotomy and an open non-radical antromastoidectomy. CONCLUSION: The diagnosis of otogenic cerebrospinal fluid (CSF) rhinorrhea is challenging and it can easily be misdiagnosed. Congenital cholesteatoma is a rare entity. We present a non-classical presentation of CC in an adult male, with a previously unreported symptom of CSF rhinorrhea. Symptomatic improvement occurred after surgical treatment of the disease.

Objective Measurements of Nasal Obstruction and Eustachian Tube Function in Pregnant Women.

Background: Hormonal changes during pregnancy have a substantial effect on the swelling of the mucous membrane in the nasal cavity, resulting in rhinitis and Eustachian tube dysfunction. The aim of the study was to assess subjective and objective changes in nasal cavity and Eustachian tube patency in the third trimester of pregnancy. Materials and Methods: The study group included fifty 18-41 year-old women in the third trimester of pregnancy. The control group consisted of 25 females aged 25 to 31 who were not pregnant. The Eustachian tube and nasal cavity patency examination was carried out using a rhinomanometer, a tympanometer and a SNOT-22 Questionnaire. Results: The SNOT-22 showed that subjective nasal obstruction was assessed as strong or worse by 42% of the study group, which was significantly higher than in the control group and confirmed with rhinomanometry. A total of 68% of the study group reported a subjective ear fullness which correlated with the week of pregnancy. The tympanometry showed that all pregnant women exhibited a type A tympanogram, but tympanometry values decreased at higher weeks of pregnancy, and statistical analysis confirmed a significant difference between the study group and the control group in tympanometry for both ears. Conclusions: The results highlight the substantial impact on both subjective and objective measurements of nasal and Eustachian tube patency. Almost every woman in the third trimester of pregnancy experiences nasal obstruction, and nearly 70% struggle with ear fullness. Recognizing and addressing these challenges are pivotal for ensuring the well-being of pregnant individuals and enhancing the quality of antenatal care.

Injury of the Hyoid Bone as a Rare Complication in Cervical Spine Rehabilitation: A Case Report.

Neck pain is a common reason for primary care visits, and its differential diagnosis should consider various conditions. The reported incidence of hyoid bone fractures is extremely low, accounting for only 0.002% of all fractures. The most common causes of hyoid bone fractures include strangulation attempts and motor vehicle accidents. We report a case of an uncommon complication of manual therapy of the cervical spine. A 76-year-old woman complained of neck pain that worsened during speaking and swallowing, originating from a neck physiotherapy session. The otolaryngological examination revealed tenderness on the right side of the neck. Flexible nasal endoscopy demonstrated a shallow right piriform recess and asymmetry of the arytenoid cartilages. Computer tomography scan of the neck showed an isolated fracture of the right greater horn (cornu major) of the hyoid bone. The treatment was nonsurgical, with the use of a Schantz collar and pain relief drugs. Reported symptoms of hyoid bone fractures include dysphagia, odynophagia, and neck pain. In most cases of hyoid fractures, conservative management suffices, involving rest, analgesic and anti-inflammatory treatment, and neck immobilization. Surgical treatment is often necessary in the cases of fractures accompanying other injuries.

The Relationship between Fine Particle Matter (PM2.5) Exposure and Upper Respiratory Tract Diseases.

PM2.5 is one of the most harmful components of airborne pollution and includes particles with diameters of less than 2.5 µm. Almost 90% of the world's population lives in areas with poor air quality exceeding the norms established by the WHO. PM2.5 exposure affects various organs and systems of the human body including the upper respiratory tract which is one of the most prone to its adverse effects. PM2.5 can disrupt nasal epithelial cell metabolism, decrease the integrity of the epithelial barrier, affect mucociliary clearance, and alter the inflammatory process in the nasal mucosa. Those effects may increase the chance of developing upper respiratory tract diseases in areas with high PM2.5 pollution. PM2.5's contribution to allergic rhinitis (AR) and rhinosinusitis was recently thoroughly investigated. Numerous studies demonstrated various mechanisms that occur when subjects with AR or rhinosinusitis are exposed to PM2.5. Various immunological changes and alterations in the nasal and sinonasal epithelia were reported. These changes may contribute to the observations that exposure to higher PM2.5 concentrations may increase AR and rhinosinusitis symptoms in patients and the number of clinical visits. Thus, studying novel strategies against PM2.5 has recently become the focus of researchers' attention. In this review, we summarize the current knowledge on the effects of PM2.5 on healthy upper respiratory tract mucosa and PM2.5's contribution to AR and rhinosinusitis. Finally, we summarize the current advances in developing strategies against PM2.5 particles' effects on the upper respiratory tract.

Planned Subtotal Resection following Stereotactic Radiosurgery of Koos 3 and 4 Vestibular Schwannomas.

Background/Objectives: Surgical resection of medium to large vestibular schwannomas (VSs, Koos grade 3 and 4) is a widely used approach, although stereotactic radiosurgery (SRS) is increasingly proposed as initial treatment. The quality of life-centered approach is challenged in cases where tumor growth control cannot be achieved with SRS, thus necessitating salvage surgery. We present a series of eight consecutive patients who required surgery due to continued tumor growth after SRS. Methods: Of the 146 patients with VS grades 3 and 4 initially treated with SRS, only eight patients (mean age, 54 ± 7.2 years; range, 42-63 years) required subsequent surgery. Their mean tumor volume was 9.9 ± 3.2 cm3. The mean time from SRS to first tumor progression and planned subtotal resection was 23 ± 5.9 months and 45 ± 17.5 months, respectively. SRS was not performed after the surgery in favor of a "wait and rescan" approach. Tumor residue was monitored on follow-up magnetic resonance imaging. In all patients, tumor growth control after planned subtotal resection was maintained at 63 ± 19.8 months. Results: None of the 146 patients had serious complications after SRS. In the eight patients who required surgery, tumor growth between 22% and 212% (mean, 4 cm3) was reported within 26 to 84 months after SRS. Before salvage surgery, they scored 1 point on the House-Brackmann scale. Subtotal excision was performed, and VIIth nerve function was preserved in all patients. At 63 ± 19.8 months, 3 patients had a House-Brackmann score of 1, four patients had a score of 2, and one patient had a score of 3. Conclusions: Surgical excision of medium to large VS after SRS can be relatively safe, provided that a quality of life-centered approach of subtotal resection is used.

Subtotal resection of vestibular schwannoma with subsequent Gamma Knife irradiation - tumor growth control, facial and cochlear nerve outcome - preliminary results.

<b>Introduction:</b> The choice of treatment of vestibular schwannoma (VS) depends on several factors, including the tumor size, the patient's age and overall health, and the presence and severity of symptoms.<b>Aim:</b> The aim of the study was to assess the effectiveness of intentional subtotal resection (STR) of tumor followed by Gamma Knife surgery (GKS) in patients with larger VS (Koos 3 and 4).<b>Materials and methods:</b> The retrospective analysis was performed on 18 patients. Data of VS volumes measured in MRI, the facial nerve function assessed in the House-Brackmann scoring system (HB), and the results of audiological examination expressed on the Gardner-Robertson scale (GR) were collected preoperatively, postoperatively, and post-GKS.<b>Results:</b> Preoperatively, the main symptom was hearing loss observed in 13 out of 18 patients. The facial nerve function was assessed as HB 1 in 16, whereas HB 2 in 2 patients. The mean volume of the tumor in the initial MRI amounted to 16.81 cm³ . Postoperatively, the facial nerve was assessed as HB 1 or 2 in 16, whereas HB 3 in 2 patients. Serviceable hearing was presented by only 4 persons. The Mean diameter of the tumor after subtotal surgery amounted to 3.16 cm³ , 1.83 cm³ after GKS, and 1.58 cm³ at the last follow-up. The facial nerve function and hearing level remained the same as before GKS in all patients.<b>Conclusions:</b> STR followed by GKS can be a safe and effective method of treatment of large VS concerning the functional outcome of the facial nerve and the tumor volume growth control.

Extracellular Vesicle-Based Drug Delivery Systems for Head and Neck Squamous Cell Carcinoma: A Systematic Review.

It is estimated that there are over 890,000 new cases of head and neck squamous cell carcinoma (HNSCC) worldwide each year, accounting for approximately 5% of all cancer cases. Current treatment options for HNSCC often cause significant side effects and functional impairments, thus there is a challenge to discover more acceptable treatment technologies. Extracellular vesicles (EVs) can be utilized for HNSCC treatment in several ways, for example, for drug delivery, immune modulation, as biomarkers for diagnostics, gene therapy, or tumor microenvironment modulation. This systematic review summarizes new knowledge regarding these options. Articles published up to 11 December 2022, were identified by searching the electronic databases PubMed/MEDLINE, Scopus, Web of Science, and Cochrane. Only full-text original research papers written in English were considered eligible for analysis. The quality of studies was assessed using the Office of Health Assessment and Translation (OHAT) Risk of Bias Rating Tool for Human and Animal Studies, modified for the needs of this review. Of 436 identified records, 18 were eligible and included. It is important to note that the use of EVs as a treatment for HNSCC is still in the early stages of research, so we summarized information on challenges such as EV isolation, purification, and standardization of EV-based therapies in HNSCC.

Susac syndrome - the current review of knowledge and own experience presentation.

Susac syndrome is a rare autoimmune vasculopathy involving the small precapillary arterioles of the brain, retina, and inner ear. It is characterized by a triad of symptoms: encephalopathy, visual disturbances due to obstruction of retinal artery branches, and sensorineural hearing loss. The study aimed to review the current medical knowledge on Susac syndrome and present our clinical experience regarding this disease entity. The paper also presents a case of a 25-year-old patient who was diagnosed with Susac's syndrome based on the clinical picture and the results of additional tests. This syndrome should be considered in the differential diagnosis of multiple sclerosis and other multifocal lesions of the central nervous system because early diagnosis of the disease and immunosuppressive treatment significantly alleviates its course and improves the prognosis.

Susac syndrome - A review of current knowledge and own experience.

Susac syndrome is a rare connective tissue disorder. The pathology affects the small vessels of the brain, retina, and inner ear, and therefore the main symptoms of the disease include encephalopathy, visual disturbances, and sensorineural hearing loss. The aim of this article is to review the current medical knowledge on Susac syndrome and to present our clinical experience regarding this disease entity. In the paper, we are also presenting a case of a 25-year-old patient who was diagnosed with Susac syndrome on the basis of clinical presentation and additional test results. Susac syndrome should be differentiated from multiple sclerosis and other causes of multifocal brain damage as early diagnosis and treatment play a key role in later prognosis.

The Latest Craniofacial Reconstructive Techniques Using Anchored Implants after Surgical Treatment of Nasal and Paranasal Sinuses Tumors.

Reconstructive surgery after surgical treatment of neoplasms in the head and neck region is always a challenge. Many factors are responsible for the success of reconstruction. The anatomy of the facial region is complex, which significantly influences the aesthetic effect of the reconstruction. Moreover, many patients undergo postoperative radiotherapy after surgical treatment, which affects the range of reconstructive techniques. The aim of this study is to review current reconstructive methods in the craniofacial region, using bone-anchored implants to attach nasal prostheses. The article also comprises the authors' own experience with successful single-stage, Vistafix 3 osseointegrated implants for the attachment of an external nasal prosthesis in a 51-year-old man after surgical removal of squamous cell carcinoma of the nose and paranasal sinuses. The literature search for articles regarding implants in craniofacial reconstructions was performed using the three following databases: Scopus, Web of Science and MEDLINE (through PubMed), and follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA). A systematic literature search was set for 2018-2023 and retrieved 92 studies. From them, 18 articles were included in the review.

Change in the Characteristics of Patients Qualified for Hearing Aids over the Last 25 Years in Poland.

Hearing loss is one of the most common causes of disability worldwide. The aim of the study was to compare the demographic structure and the results of hearing tests in people qualified for hearing aids over the last 25 years. The material covered 1246 patients qualified for hearing aids in the years 1996-2001 and 2016-2021. Patients were divided into two groups according to the time of qualifying for hearing aids. Group 1 (G1) consisted of 759 people qualified in the years 1996-2001, and Group 2 (G2) comprised 487 people qualified in the years 2016-2021. Statistical analysis was performed on the results of pure tone threshold audiometry and the demographic structure in both groups. Patients in G1 had statistically significantly elevated hearing thresholds (HT) in the air conduction range at frequencies from 2000 to 8000 Hz in relation to G2 patients. The opposite situation was observed for the bone conduction threshold. G2 patients had significantly elevated bone conduction HT at frequencies from 250 to 1000 Hz compared to G1 patients. The age structure in both groups was similar; however, the gender distribution was statistically significantly different. In G1 women accounted for 40%, and in G2, they became the dominant gender (53%). Over the last twenty years, there has been a change in the structure of patients qualified for hearing aids. Although the age has remained similar, today, patients decide to use hearing aids at an earlier stage of hearing loss than 25 years ago. Modern women began to use hearing aids much more often.

The Impact of the Angular Head Movement's Velocity during Diagnostic Maneuvers on Proper Benign Positional Paroxysmal Vertigo Diagnosis and Therapy.

Based on the current state of the BPPV field, there are no guidelines that specify an angular head movement's velocity (AHMV) during diagnostic maneuvers of BPPV. The aim of this study was to evaluate the impact of AHMV during diagnostic maneuvers on proper BPPV diagnosis and therapy. The analysis covered the results obtained in 91 patients with a positive result of the Dix-Hallpike (D-H) maneuver or the roll test. The patients were divided into four groups based on values of AHMV (high 100-200°/s and low 40-70°/s) and the BPPV type (posterior: PC-BPPV or horizontal: HC-BPPV). The parameters of the obtained nystagmuses were analyzed and compared to AHMV. There was a significant negative correlation between AHMV and latency of nystagmus in all study groups. Furthermore, there was a significant positive correlation between AHMV and both maximum slow phase velocity and average frequency of nystagmus in the PC-BPPV groups, whereas it was not observed in the HC-BPPV patients. Complete relief of symptoms was reported after 2 weeks and was better in patients diagnosed with maneuvers performed with high AHMV. High AHMV during the D-H maneuver allows the nystagmus to be more visible, increasing the sensitivity of diagnostic tests and is crucial for a proper diagnosis and therapy.

A Relation between Obstructive Sleep Apnea in Pregnancy and Delivering Small for Gestational Age Infant-A Systematic Review.

Obstructive sleep apnea (OSA) during pregnancy can negatively affect both the mother and the baby. Our main goal is to show whether there is an association between OSA during pregnancy and delivering small for gestational age (SGA) infants. This systematic review was conducted according to the PRISMA 2020 statement using three databases: MEDLINE via PubMed, Scopus, and Cochrane Library. All databases were last accessed on 1 June 2023. The implemented systematic literature search identified 744 articles. After excluding reviews, meta-analyses, book chapters, case reports, and letters, 47 studies were analyzed, 18 of which finally met the inclusion criteria. The included studies mainly indicate that OSA during pregnancy may not significantly impact SGA, but some of them have shown the existence of this relation. Nevertheless, it is recommended that all pregnant women should be screened for symptoms of OSA and that sleep tests should be performed on those who show signs of it. Detecting and treating OSA early in pregnancy can help reduce the condition's negative effects. However, more extensive studies are still needed to gather clear evidence on the impact of an OSA diagnosis on mothers and babies.

HMGB1 Carried by Small Extracellular Vesicles Potentially Plays a Role in Promoting Acquired Middle Ear Cholesteatoma.

Cholesteatoma is a specific medical condition involving the abnormal, non-cancerous growth of skin-like tissue in the middle ear, potentially leading to a collection of debris and even infections. The receptor for advanced glycation (RAGE) and its ligand, high-mobility box 1 (HMGB1), are both known to be overexpressed in cholesteatoma and play a potential role in the pathogenesis of the disease. In this study, we investigated the role of small extracellular vesicles (sEVs) in carrying HMGB1 and inducing disease-promoting effects in cholesteatoma. No significant differences in the concentration of isolated sEVs in the plasma of cholesteatoma patients (n = 17) and controls (n = 22) were found (p > 0.05); however, cholesteatoma-derived sEVs carried significantly higher levels of HMGB1 (p < 0.05). In comparison to sEVs isolated from the plasma of controls, cholesteatoma-derived sEVs significantly enhanced keratinocyte proliferation and IL-6 production (p < 0.05), potentially by engaging multiple activation pathways including MAPKp44/p42, STAT3, and the NF-κB pathway. Thus, HMGB1(+) sEVs emerge as a novel factor potentially promoting cholesteatoma progression.

Atopy as a specific predictor of response to systemic and local steroid therapy in patients with chronic rhinosinusitis without nasal polyps.

<b>Introduction:</b> Studies on the pathophysiology of chronic rhinosinusitis have shown an effect of IgE antibodies on the course of the disease, as well as the effectiveness of treatment. Steroid therapy remains the most prevailing method of CRS treatment. </br></br> <b>Aim: </b>The aim of our study was to determine the clinical response to systemic and local steroid therapy in patients with CRSsNP depending on the total IgE antibody serum concentration. </br></br> <b>Material and methods:</b> A total of 92 patients with CRSsNP took part in the study, where they were divided randomly into 2 groups. In group I, the patients received fluticasone propionate 800 mcg/day intranasally for 12 weeks. Patients in group II were treated with prednisone at a dose of 0.5 mg/kg/day, given orally, for 7 consecutive days and continued by another week with decreasing dosage. Both groups were evaluated prior to and following treatment using the TSS score of CRS clinical symptoms, the endoscopic Lund-Kennedy scale and the Lund-Mackay CT staging of chronic rhinosinusitis. Statistical analy-sis of the effectiveness of treatment was carried out in subgroups according to the total IgE serum concentrations obtained before treatment. </br></br> <b>Results:</b> Both groups of patients achieved statistically significant improvement in the TSS evaluation, as well as in endosco-pic and CT imaging findings. In patients with a total IgE serum concentration over 100 IU/ml systemic steroid therapy sho-wed significantly greater effect on the relief of CRS symptoms in the TSS score than intranasal steroid therapy. Analogous differences in the effectiveness of both methods were not found in patients with a normal total IgE serum concentration (<100 IU/ml). </br></br> <b>Conclusions:</b> A short course of systemic steroid therapy is more effective than local treatment in relieving of CRS symptoms in patients with CRSsNP with elevated serum concentration of IgE antibodies. Atopy may be considered a specific predictor of response to steroid therapy in the treatment of chronic rhinosinusitis.

The Overlap Syndrome of Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease: A Systematic Review.

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are common diseases that strongly impact the quality and length of life. Their coexistence is determined by overlap syndrome (OS). This systematic review aims to define the significance of these comorbidities according to the current state of knowledge. For this systematic review, we searched PubMed, Scopus, and Cochrane for studies published between 2018 and 26 October 2022, to find original, observational, human studies published in English, where the diagnosis of COPD was according to the Global Initiative for Obstructive Lung Disease guidelines and the diagnosis of OSA was based on polysomnography. The quality of studies was assessed using the Newcastle-Ottawa quality assessment tool for cohort and case-control studies, as well as its modification for cross-sectional studies. Of the 1548 records identified, 38 were eligible and included in this systematic review. The included studies covered a total population of 27,064 participants. This paper summarizes the most important, up-to-date information regarding OS, including the prevalence, meaning of age/gender/body mass index, polysomnography findings, pulmonary function, comorbidities, predicting OSA among COPD patients, and treatment of this syndrome.