Manuel Bernal-Sprekelsen

• M.D.. PH.D.
• Chair at University of Barcelona

Background The aim of the present study was to evaluate the sex-disparities in larynx cancer patients treated with CO2-Transoral Laser Microsurgery (CO2-TOLMS). Methods Retrospective analysis of 1290 consecutive patients. Oncologic and functional outcomes were evaluated according to sex groups. Survival rates were compared by propensity-score matc...

The introduction of biologics for the treatment of severe upper and lower (type 2) airway inflammation has been a gamechanger in the management of these diseases. Biologics are injectable medications targeting different molecules relevant in (type 2) inflammation in patients with severe (type 2) airway diseases, like asthma, eosinophilic chronic ob...

Remission has recently been proposed as the new goal of care in CRSwNP or Nasal Polyp Syndrome by the European Forum for Research and Education in Allergy and Airway Diseases / European Position Paper on Rhinosinusitis and Nasal Polyps (EUFOREA/EPOS) (1,2) as well as by global leaders in Rhinology (3). In CRSwNP, remission is defined as a prolonged...

Purpose This study proposes the Lamella Ostium Extent Mucosa (LOEM) system as a compact and user-friendly classification for endoscopic sinus surgery (ESS), based on surgical bone extension and mucosal management, aiming to resolve inconsistencies in describing surgical techniques and extension levels, and to enhance comparability of outcomes in ch...

Background/Objectives: Sinonasal mucosal melanomas (SNMMs) are rare and aggressive malignancies with poor survival outcomes. Our systematic review and meta-analysis aim to evaluate overall survival (OS) rates in patients with SNMM; Methods: We conducted a systematic search, following PRISMA guidelines across PubMed, Web of Science (WOS), and citati...

Background: In the absence of direct evidence supporting how to use nasal endoscopy findings to judge chronic rhinosinusitis (CRS) disease control, experts' practice patterns could provide guidance. Methodology: Participants consisted of a diverse group of twenty-nine rhinologists. Participants were presented with every possible combination of bila...

Objectives The peer review process is critical to maintaining quality, reliability, novelty, and innovation in the scientific literature. However, the teaching of scientific peer review is rarely a component of formal scientific or clinical training, and even the most experienced peer reviewers express interest in continuing education. The objectiv...

Background Surgical closure of large nasoseptal perforation (NSP) is challenging. The use of an extended anterior ethmoidal artery (eAEA) flap to reconstruct NSP may present with difficulties for NSPs which have their upper edge in a high position. Method We propose adding a “donut-shape” flap from surrounding septal tissue to the eAEA flap. Thus,...

Objective To report a single-centre experience in the endoscopic carbon dioxide laser-assisted approach to glomus tympanicum tumours. Methods A retrospective case review was conducted of patients diagnosed with class A1 to B1 glomus tympanicum tumours who underwent exclusive transcanal endoscopic carbon dioxide laser surgery. Results Seven patien...

Asthma, which affects some 300 million people worldwide and caused 455,000 deaths in 2019, is a significant burden to suffers and to society. It is the most common chronic disease in children and represents one of the major causes for years lived with disability. Significant efforts are made by organizations such as WHO in improving the diagnosis,...

Severe chronic rhinosinusitis with nasal polyps (CRSwNP), a form of diffuse bilateral (usually type 2) CRS, is a debilitating disease with a significant impact on quality of life (QoL). With novel knowledge and treatment options becoming available, there is a growing need to update or revise key definitions to enable communication across different...

Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals and/or aspirin treatment...

This chapter specifically considers the complications associated with endoscopic sinus surgery, starting with a means of classification before discussing the details of complications based on the primary domains of vascular trauma, neurological sequelae and orbital complications. The text includes methods tips and pearls of wisdom for preventing an...

Background: Chronic rhinosinusitis (CRS) disease control is a global metric of disease status for CRS. While there is broad acceptance that it is an important treatment goal, there has been inconsistency in the criteria used to define CRS control. The objective of this study was to identify and develop consensus around essential criteria for asses...

Background Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represents a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and present...

Severe chronic rhinosinusitis with nasal polyps (CRSwNP) is a debilitating disease with a significant impact on the quality of life (QoL). It is typically characterized by a type 2 inflammatory reaction and by comorbidities such as asthma, allergies and NSAID-Exacerbated Respiratory Disease (N-ERD). Here, the European Forum for Research and Educati...

Cerebrospinal fluid (CSF) rhinorrhea may be classified as traumatic and nontraumatic. The clinical presentation of CSF rhinorrhea includes unilateral watery drainage with a characteristic metallic or salty taste, often in the clinical setting of possible etiologic factors. Conservative treatment is recommended in cases of CSF leaks due to nonsurgic...

Introduction CO2 transoral laser microsurgery (CO2-TOLMS) has pushed the indications of partial surgery of the larynx regardless the age of the patient. Objective To evaluate the complications and the oncologic and functional outcomes of CO2-TOLMS in patients older and younger than 70 years. Methods Retrospective analysis of 1244 consecutive lary...

Transoral surgery (TOS) is a minimally invasive surgical approach to laryngeal cancer that includes different techniques, based on the system used for visualization (microscope or videoendoscope), the instruments employed for the resection (laser, monopolar spatula, ultrasound forceps, etc.), and the potential assistance of a robotic platform. Amon...

Background and objective Minimally invasive surgery of benign middle ear tumours is possible by using the endoscope. The optimal lighting and the broadest vision it offers, allow a transcanal approach to these rare tumours. The objective of this work is to summarise its key points through a case series. Materials and methods Retrospective study of...

Background: Sinonasal mucosal melanoma is an aggressive malignancy with a 5-year survival rate ranging from 20% to 39%. Despite the evolving surgical and radiotherapy techniques, and introduction of immune-checkpoint inhibitor therapy, overall survival rates remain poor. Methodology: A retrospective cohort study was conducted at the Hospital Cli...

They are usually discovered by chance in routine radiologic examinations of the sinuses in around 1% [1]. The overall incidence of paranasal sinus osteomas in patients with coronal sinonasal CT scans due to sinonasal symptoms has been calculated at 3% [2]. Osteomas can be found starting from the second to the sixth decade, with a predilection of fi...

Sinonasal neoplasms are not very common, as they account only for 1% of all malignancies [1] and for 3% of all upper respiratory tract malignancies and accounting for only 3–5% of all head and neck malignancies [2, 3]. Annual incidence can be relatively high in Asian and African populations, the highest age-adjusted rates, between 2.5 and 2.6 per 1...

Objectives/hypothesis To present a modified endoscopic medial maxillectomy (MEMM) approach to control maxillary sinus pathologies. Methods MEMM was completed in 13 fresh-frozen specimens. An MEMM includes cutting the nasolacrimal duct, inferior meatus flap, and repositioning the inferior turbinate (IT). The following measurements were obtained: le...

Purpose SARS-CoV-2 vaccines are a key step in fighting the pandemic. Nevertheless, their rapid development did not allow for testing among specific population subgroups such as pregnant and breastfeeding women, or elaborating specific guidelines for healthcare personnel working in high infection risk specialties, such as otolaryngology (ORL). This...

Background To evaluate the importance of larynx compartments in the prognosis of T3-T4a laryngeal cancer treated with transoral laser microsurgery. Methods Two hundred and two consecutive pT3-T4a larynx carcinomas. Pre-epiglottic space involvement, anterior and posterior paraglottic space (PGS) involvement, vocal cord, and arytenoid mobility were...

Resumen Antecedentes y objetivo La cirugía mínimamente invasiva de tumores benignos del oído medio es posible mediante el uso del endoscopio. La mejor iluminación y la visión más amplia que ofrece permiten el abordaje transcanal de estos raros tumores. El objetivo del presente trabajo es sintetizar los puntos clave de su diagnóstico y tratamiento,...

Objective To determine the effectiveness of a soft-tissue bulking agent comparing novel approaches of Eustachian tube (ET) augmentation procedures: transpalatinatal Eustachian tube augmentation in local and general anesthesia versus an augmentation with velotraction under general anesthesia. The clinical endpoint was the resolution of symptoms rela...

Resumen Propósito A instancias de la Organización Médica Colegial, elaborar un nuevo nomenclátor de actos y procedimientos médicos en Otorrinolaringología basado en la Clasificación Internacional de Enfermedades CIE-9-MC. Estipular los principios generales y definir criterios e indicadores cuantitativos y cualitativos que puedan determinar el bare...

Background The question of an optimal strategy and outcomes in COVID-19 tracheostomy has not been answered yet. The critical focus in our case study is to evaluate the outcomes of tracheostomy on intubated COVID-19 patients.MethodsA multicentric prospective observational study of 1890 COVID-19 patients undergoing tracheostomy across 120 hospitals w...

Purpose: SARS-CoV-2 vaccines are a key step in fighting the pandemic. Nevertheless, their rapid development did not allow for testing among specific population subgroups such as pregnant and breastfeeding women, or elaborating specific guidelines for healthcare personnel working in high infection risk specialties, such as otolaryngology (ORL). This...

Background Since the outbreak in China due to coronavirus disease 2019 (COVID-19) various studies have been published describing olfactory and gustatory dysfunction (OGD).Objective The aim was to investigate the frequency and severity of OGD in SARS-CoV-2 (+) out-patients compared to controls with common cold/flu like symptoms and two negative RT-P...

IntroductionThe aim of our study was to obtain data about the contagion rate among Otolaryngologists in Spanish ENT Departments and about the clinical outcomes in positive otolaryngologists. As a secondary objective, we aim to assess the rate of contagion in the first and the second Covid-19 wave in Spain among Otorhinolaryngologists and the region...

This is a reply letter to the manuscript “The size and diameter of pieces of cartilage are not fixed for the palisade technique and one-piece technique”, regarding the elevation of a tympanomeatal flap and keratin pearl formation in “Palisade cartilage tympanoplasty compared to one-piece composite cartilage-perichondrium grafts for transcanal endos...

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updat...

The current COVID-19 pandemic has rendered up to 15% of patients under mechanical ventilation. Because the subsequent tracheotomy is a frequent procedure, the three societies mostly involved (SEMICYUC, SEDAR and SEORL-CCC) have setup a consensus paper that offers an overview about indications and contraindications of tracheotomy, be it by puncture...

The current COVID-19 pandemic has rendered up to 15% of patients under mechanical ventilation. Because the subsequent tracheotomy is a frequent procedure, the three societies mostly involved (SEMICYUC, SEDAR and SEORL-CCC) have setup a consensus paper that offers an overview about indications and contraindications of tracheotomy, be it by puncture...

IMPORTANCE The current coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented needs for invasive ventilation, with 10% to 15% of intubated patients subsequently requiring tracheotomy. OBJECTIVE To assess the complications, safety, and timing of tracheotomy performed for critically ill patients with COVID-19. DESIGN, SETTING, AND PART...

The current COVID-19 pandemic has rendered up to 15% of patients under mechanical ventilation. Because the subsequent tracheotomy is a frequent procedure, the three societies mostly involved (SEMICYUC, SEDAR and SEORL-CCC) have setup a consensus paper that offers an overview about indications and contraindications of tracheotomy, be it by puncture...

PurposeThe endoscopic approach to tympanoplasty is gaining popularity, but its adoption for the palisade tympanoplasty technique is unstudied. The aim of the present study was to evaluate the effectiveness of endoscopic cartilage palisade tympanoplasty compared to one-piece composite cartilage-perichondrium grafts for tympanic membrane closure in a...

Background Chronic rhinosinusitis (CRS) is a chronic inflammatory disease associated with a substantial personal and socioeconomic burden. Monitoring of patient‐reported outcomes by mobile technology offers the possibility to better understand real‐life burden of CRS. Methods This study reports on the cross‐sectional evaluation of data of 626 user...

Resumen La alta incidencia de insuficiencia respiratoria aguda en el contexto de la pandemia por COVID-19 ha conllevado el uso de ventilación mecánica hasta en un 15%. Dado que la traqueotomía es un procedimiento quirúrgico frecuente, este documento de consenso, elaborado por 3 Sociedades Científicas, la SEMICYUC, la SEDAR y la SEORL-CCC, tiene com...

Resumen La alta incidencia de insuficiencia respiratoria aguda en el contexto de la pandemia por COVID-19 ha conllevado el uso de ventilación mecánica hasta en un 15%. Dado que la traqueotomía es un procedimiento quirúrgico frecuente, este documento de consenso, elaborado por tres Sociedades Científicas, la SEMICYUC, la SEDAR y la SEORL-CCC, tiene...

Resumen La alta incidencia de insuficiencia respiratoria aguda en el contexto de la pandemia por COVID-19 ha conllevado el uso de ventilación mecánica hasta en un 15%. Dado que la traqueotomía es un procedimiento quirúrgico frecuente, este documento de consenso, elaborado por tres Sociedades Científicas, la SEMICYUC, la SEDAR y la SEORL-CCC, tiene...

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012(1-3). The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides a...

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an upd...

Purpose Intense bleeding of the surgical field is a potential factor influencing success of functional endoscopic sinus surgery (FESS). Hypotensive anesthesia with α2 intravenous agonists reduces intraoperative bleeding, but which is the best agent is unknown. The main objective of this trial was to compare the current standard adjuvant drug for hy...

Background: The European Position Papers on Rhinosinusitis from 2005, 2007 and 2012 have had a measurable impact on the way this common condition with high impact on quality of life is managed around the world. EPOS2020 will be the latest iteration of the guideline, addressing new stakeholders and target users, presenting a summary of the latest l...

In 1994 a decision analysis, based on the literature and utility ratings for outcome by a panel of experienced head and neck physicians, was presented which showed a threshold probability of occult metastases of 20% to recommend elective treatment of the neck. It was stated that recommendations for the management of the cN0 neck are not immutable a...

Introduction Since 2015, the European Laryngological Society (ELS) has organized on a yearly basis the European Laryngological Live Surgery Broadcast. The goal of this paper is to demonstrate the increasing worldwide audience. Material and methods The number of individual computers logged in, number of estimated audience, and number of countries w...

Background Data about the results of transoral laser microsurgery (TLM) in elderly patients are limited. Methods A retrospective study of 72 consecutive cases of glottic carcinoma (63 pT1 and 9 pT2 cases) in elderly patients (≥70 years old, mean 76 years) treated with TLM was made. A systematic review of the literature was performed. Results Six...

Background Indications of transoral laser microsurgery (TLM) are conditioned by the risk of local relapse. Objective To evaluate prognostic factors of local relapse and local control with TLM (LC‐TLM). Methods Local relapse and LC‐TLM were evaluated in 1119 patients. Logistic regression and CHAID decision tree analysis were performed. Results Lo...

Purpose Management of the facial nerve is instrumental in the surgical treatment of parotid cancer. Methods A literature search was conducted using PubMed and ScienceDirect database. A total of 195 articles were finally included into the analysis, based on relevance, scientific evidence and actuality. Results In the majority of cases the facial n...

Background: The nasal floor and inferior meatus (NFIM) flap represents an available option for the reconstruction of a septal perforation (SP). This study explores the feasibility of repairing SPs using a modified simple and extended (including inferior turbinate) NFIM flap. Methods: An anatomic study was achieved in fresh frozen cadaveric speci...

Mobile health technology is emerging to take a prominent position in the management of chronic diseases. These technologies aim at enhancing patient empowerment via education and self-management. To date, of all the different apps available for patients with sinus disease, none were developed by medical experts dealing with chronic rhinosinusitis (...

Background: The accuracy of white light endoscopy in combination with narrow band imaging (WLE + NBI) for diagnosis of squamous cell carcinoma (SCC) does not reach 100%. We evaluated the characteristics of the false-negative and false-positive cases. Methods: Five hundred thirty lesions of the upper airways were evaluated. The WLE was followed b...

Mobile health technology is emerging to take a prominent position in the management of chronic diseases. These technologies aim at enhancing patient empowerment via education and self-management. To date, of all the different apps available for patients with sinus disease, none were developed by medical experts dealing with chronic rhinosinusitis (...

Purpose: We assessed the evidence for the use of α2-adrenergic agonists (A2AAs) in bleeding control and field quality in endoscopic sinus surgery. Methods: We systematically reviewed randomized clinical trials (RCTs) assessing A2AAs in endoscopic sinus surgery. Abstracts were reviewed by 2 investigators for eligibility, and selected articles wer...

The first Rhinology Future Debates was held in Brussels in December 2016, organized by EUFOREA (European Forum for Research and Education in Allergy and Airways diseases). The purpose of these debates is to bring novel developments in the field of Rhinology to the attention of the medical, paramedical and patient community, in a highly credible and...

The first Rhinology Future Debates was held in Brussels in December 2016, organized by EUFOREA (European Forum for Research and Education in Allergy and Airways diseases). The purpose of these debates is to bring novel developments in the field of Rhinology to the attention of the medical, paramedical and patient community, in a highly credible and...

ORL-students and residents have an ongoing debate about the “best” programme in Europe. Aim of this study was to comparatively assess differences among programmes in training, satisfaction, quality of life (QoL) of residents and recent otorhinolaryngologist (ORL) specialists in France, Germany, Spain, Italy, Austria, and Belgium. A self-administere...

Objectives/hypothesis: Endonasal surgeries are the primary cause of septal perforation (SP). However, trauma, inflammation, infections, neoplasms, or abuse of inhaled drugs can also cause SP. Septal repair is indicated in patients who experience nasal obstruction, crusting, intermittent epistaxis, purulent discharge, or nasal whistling and in thos...

Background: The purpose of this study was to evaluate the value of narrow band imaging (NBI) examination in the office for the diagnosis and follow-up of upper airway premalignant and malignant lesions. Methods: Four hundred eighty lesions were evaluated with white light endoscopy (WLE) and NBI before a biopsy/excision. Additionally, 151 premali...

Background: Cervico-mediastinal hemangiomas in adulthood are rare and slow-growing vascular tumors. The optimal treatment for giant hemangiomas is controversial. In asymptomatic cases, clinical observation is generally recommended. Methods: We report the transoral resection of a pharyngolaryngeal hemangioma (diameters of 44 × 56 × 39 mm) with tr...

Precision medicine (PM) is increasingly recognized as the way forward for optimizing patient care. Introduced in the field of oncology, it is now considered of major interest in other medical domains like allergy and chronic airway diseases, which face an urgent need to improve the level of disease control, enhance patient satisfaction and increase...

Objectives/hypothesis: To evaluate the versatility of the pericranial flap (PCF) to reconstruct the ventral skull base, using the frontal sinus as a gate for its passage into the sinonasal corridor "money box approach." Study design: Anatomic-radiological study and case series. Methods: Various approaches and their respective defects (cribrifo...

Juvenile angiofibroma is an uncommon, benign, locally aggressive vascular tumor. It is found almost exclusively in young men. Common presenting symptoms include nasal obstruction and epistaxis. More advanced tumors may present with facial swelling and visual or neurological disturbances. The evaluation of patients with juvenile angiofibroma relies...

Endoscopic approaches to the paranasal sinuses and skull base. A step-by-step anatomic dissection guide.

OBJECTIVE Different surgical routes have been used over the years to achieve adequate decompression of the optic nerve in its canal including, more recently, endoscopic approaches performed either through the endonasal corridor or the transorbital one. The present study aimed to detail and quantify the amount of bone removal around the optic canal,...

Background and objectives: Previous studies showed good short-term Quality of life (QOL) after Transoral Laser Microsurgery (TLM) for laryngeal cancer. Here, we aimed to evaluate QOL after TLM in the long-term. Methods: Prospective longitudinal study. Sixty-two consecutive disease-free patients were evaluated using UW-QOL v4 and SF-12 questionna...

Objectives: Endoscopic resection has become an established surgical option for most juvenile nasopharyngeal angiofibromas (JNA). However, surgical management of JNA with intracranial extension remains challenging. This retrospective multicenter study reviews a series of patients with advanced stage JNA treated via endonasal/endoscopic approach. Met...

Little is known about the long-term effects of either transnasal transsphenoidal endoscopic approach (TTEA) or expanded endonasal approach (EEA). This study assessed the long-term impact of endoscopic skull base surgery on olfaction, sinonasal symptoms, mucociliary clearance time (MCT), and quality of life (QoL). Patients with pituitary adenomas un...

Europe-wide efforts are being initiated to define quality standards and harmonize Otolaryngology, Head and Neck Surgery (ORL-HNS)-specialty-training by creating an European board examination. However, differences within and between countries remain and are underinvestigated making comparisons and further improvement more difficult. The study aimed...

Objectives: Endoscopic resection has become an established surgical option for most juvenile nasopharyngeal angiofibromas (JNA). However, surgical management of JNA with intracranial extension remains challenging. This retrospective multicenter study reviews a series of patients with advanced stage JNA treated via endonasal/endoscopic approach. M...

The frontal recess and frontal sinus anatomy can vary from simple to complex. The variations in the anatomy of the frontal recess and frontal sinus are considerable but almost all variations can be classified if the various cell patterns are analyzed. This consensus document was developed to improve the ability of the surgeon to understand these po...

Background: The body of knowledge regarding rhinosinusitis(RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Conse...

Background: Controversy exists regarding treatment of advanced laryngeal cancer. The purpose of this study was to evaluate the oncologic and functional outcomes of T3 to T4a supraglottic squamous carcinomas treated with transoral laser microsurgery (TLM). Methods: We conducted a retrospective analysis from an SPSS database. Primary outcomes were...

Transoral Laser Microsurgery of Benign and Malignant Lesions.

Objective: To study the long-term radiological findings after endonasal endoscopic approach to the skull base. Material and methods: Prospective study that included 55 patients who underwent advance endoscopic skull base surgery. All patients were evaluated with MRI before, 3 months and 12 months after surgery. We used the Lund-Mackay staging sy...

Introduction: Local progression of papillary thyroid carcinoma (PTC) after failure of standard therapies may cause pain, ulceration, and bleeding. As patients are fully aware of the tumor growth, they might suffer high grade anxiety. Electrochemotherapy (ECT) is a new local palliative treatment for skin metastases of malignant melanoma or other tu...

Background: The use of adjuvant hypotensive drugs during anaesthesia might reduce bleeding and thus reduce risks during surgery. As intense bleeding during functional endoscopic naso-sinusal surgery (FESS) hinders the visualization of the surgical field, some anesthetists use them in clinical practice despite the lack of objective evidence on the e...

Significant bleeding during functional endoscopic naso-sinusal surgery (FESS) impairs recognition of anatomical references and may negatively affect surgical outcome. Anaesthesia including clonidine as an adjuntive hypotensive agent may reduce intraoperative bleeding. A randomised comparison of clonidine-based vs remifentanil-based hypotensive anae...

The aim of this radio-anatomical study is to ensure that the potential donor area of the pedicled lateral nasal wall flap (PLNW) is adequate to reconstruct nasal perforation. Analysis was conducted on 40 de-identified CT angiographies. The area and length of the PLNW, the septum, and the nasal floor were measured. In a cadaver study, 20 hemi-crania...

Background: Granulation tissue after transoral laser microsurgery can make it difficult to distinguish between normal healing and tumour recurrence. Materials and methods: We carried out a retrospective analysis of 316 consecutive glottic carcinomas (Tis-T3). Presence of granulation tissue at one and six months was correlated with demographic an...

We thank the authors, the editors, and all the anonymous referees who have contributed to this special issue.