Left Maxillary Sinus Research Articles

Nasal and maxillary sinus volume change in patients with obstructive sleep apnea after bimaxillary advancement surgery

The airway complex is modified by bimaxillary advancement surgery performed in patients suffering from obstructive sleep apnea (OSA). The aim of the present study is to analyse the volume of nasal and maxillary sinus after bimaxillary advancement surgery in patients suffering from OSA. The maxillary sinus and nasal complex of eighteen patients with OSA was measured through cone-beam computed tomography (CBCT) before and after they were treated with bimaxillary advancement surgery. Digital planning software was used to effectively measure the upper volume changes, as well as, statistical analysis of the results was performed.Methods Eighteen patients were diagnosed with OSA the severity of which was measured by the apnea hypopnea index and were selected and submitted to preoperative and postoperative CBCT scans. Afterwards, datasets were uploaded into therapeutic digital planning software (Dolphin Imaging) to measure the volume of the right and left maxillary sinus and nasal and maxillary sinus complex. Statistically analysis between preoperative and postoperative measures was performed by Student t-test statistical analysis.Results The paired t-test showed statistically significant volumetric reductions in the left maxillary sinus (p = 0.0004), right maxillary sinus (p < 0.0001) and nasal and maxillary sinus complex (p = 0.0009) after bimaxillary advancement surgery performed in patients suffering from OSA.Conclusion The results showed that bimaxillary advancement surgery reduces the maxillary sinus volume as well as, the fossa nasal and sinus complex volume.

Maxillary Sinus Epidermoid Cyst: A Case Report.

The preoperative diagnosis of a paranasal epidermoid cysts (EC) is challenging and is frequently mistaken. We present the case of a patient who developed a swelling on the left side of the face. The clinical examination showed a fixed and poorly defined swelling in the left maxillary region, with a slightly painful bulge in the upper vestibular peri-gingival area. A computed tomography (CT) scan showed a well-encapsulated expansive hypodensity that filled the left maxillary sinus. Magnetic resonance imaging (MRI) revealed a mass hypo-intense on T1-weighted images, high intense on T2-weighted images, hyperintense on diffusion-weighted images, and had a low apparent diffusion coefficient with no contrast uptake observed after the injection of Gadolinium. Surgical excision under general anesthesia was considered. A combined approach using an endoscopic sinus and Caldwell-Luc approach was performed and the histopathological examination confirmed the diagnosis of an EC. In conclusion, the preoperative imaging, including CT scans and MRI, aids in diagnosing ECs and differentiating them from other sinus tumors. Postoperative follow-up involving endoscopic surveillance and CT scans is crucial to monitor for potential recurrence.

Aggressive odontogenic myxoma of the maxilla in a 9-year-old child. Report of a case and literature review

Odontogenic myxoma is a rare, locally aggressive benign tumour of odontogenic ectomesenchyme origin. The tumour may cause signifi cant facial disfi gurement and has a negative psychological impact on a child. Odontogenic myxoma has predilection for females in the second and third decades of life. The mandibular molar region is the most frequently affected site. It is imperative to detect the tumour early to avoid radical surgery and reduce local recurrences. This case study reports a case of a 9-year-old female patient who presented with an expansile tumour that affected the entire left maxilla, perforated into the left maxillary sinus and completely occluded the sinus.

Maxillary Sinus Carcinoma Presenting as Trochlear Nerve Palsy

We present a case of 21-year old gentleman presented with diplopia for last 4 months. There was history of protrusion of left eye ball, abnormal head posture causing head tilt and turning face towards right side and a painless lump in mouth over hard palate on left side. On examination, there was torticollis of the head with proptosis and partial ptosis of the left eye. There was impairment of intorsion, depression and adduction of the left eye with binocular diplopia which worsened when the left eye was directed downwards and medially. There was sensory loss in ophthalmic and maxillary divisions of the left Trigeminal nerve. CT scan of the paranasal sinuses revealed a locally aggressive mass in the left maxillary sinus with erosion and extension to left temporal bone. Biopsy confirmed it as Maxillary Sinus Carcinoma and a multidisciplinary management with ENT, neurosurgery and oncology was planned.

Prevalence of Incidental Maxillary Sinus Anomalies on CBCT Scans: A Radiographic Study.

CBCT significantly impacts dental procedures and has brought significant reforms to our approach to diagnosis and treatment planning despite its limitations in differentiating soft tissues. It is an excellent imaging modality and quickly identifies sinus opacification and provides valuable insight into paranasal sinus pathologies, with considerably lower radiation exposure. The present study aimed to investigate the occurrence of maxillary sinus abnormalities in CBCT scans, identify the frequency, type, and location of these findings, and find the correlation between the distance of periapical lesions and radiographic changes in the maxillary sinus. Two examiners independently evaluated 117 patients to diagnose and classify the cases into different abnormality subtypes. The periapical lesions most closely related to the sinus were recorded. The diameters of the left and right maxillary sinus ostium and the distance of the ostium's lower border to the sinus's osseous floor were recorded. The findings were correlated with the age and gender of these patients. The present study reveals that sixty-one patients were diagnosed with mucosal thickening (52.1%). The sinus wall most affected by mucosal thickening was the maxillary sinus floor, followed by the medial and lateral walls. Of 19 patients with periapical lesions, 15 had maxillary sinus mucosal thickening, which is statistically significant (p = 0.004). The high occurrence of abnormalities in the maxillary sinus emphasizes the importance for the radiologist to comprehensively interpret the whole volume acquired in CBCT images, including the entire sinus. Incidental findings may be considered in the individual clinical context of signs and symptoms, reducing the risk of overestimating the real impact of radiographic findings.

Evaluation of Maxillary Sinus Volume of Class III Individuals with Different Jaw Positions by Cone-Beam Computed Tomography.

To compare maxillary sinus volumes and surface areas among individuals with Class III skeletal patterns, with different sagittal positions of maxilla and Class I patients with normal jaw positions using cone-beam computed tomography (CBCT). CBCT images of 168 patients were analyzed retrospectively. The calculated surface areas and sinus volumes of 58 patients with Class I, normal mandibular and maxillary position (0<ANB<4, 84>SNA>80, 82>SNB>78) were compared with 61 patients with Class III retrognathic maxillary and normal mandibular positions (MRs) (ANB<0, SNA<80, 82>SNB>78) and 49 patients with Class III normal maxillary and prognathic mandibular positions (MP) (ANB<0, 84>SNA>80, SNB>82). Also, volume differences between genders and sides were investigated. One-way ANOVA and t-test were used to compare age, gender, skeletal patterns, and maxillary sinus measurements. CBCT images of 94 females and 74 males were examined. There was no statistically significant difference in the right and left maxillary sinus volume and surface area measurements among Class I, Class III MR, and Class III MP groups (p>0.05). When the maxillary sinus volume and surface area were evaluated according to gender, the right maxillary sinus surface area and volume of males were found to be statistically significantly higher than those of females (p=0.012 and p=0.024). Similarly, the left maxillary sinus surface areas and volumes of males were also found to be significantly higher than those of females (p=0.000 and p=0.002). Different sagittal positions of the maxilla do not appear to affect maxillary sinus volume, and males tend to have greater maxillary sinus volume than females. CBCT images can be used to calculate intrabony air spaces.

Cutaneous anthrax associated with facial palsy: A case report

Rationale: Anthrax is a zoonotic disease caused by spores of Gram-positive Bacillus anthracis, commonly affects mammals and in rare cases birds. Human infection occurs accidentally through direct or indirect exposure to animal or their products. Patient concerns: A 63-year-old man was referred to our hospital with flu-like symptoms and severe swelling and redness on the face, the roof of the mouth, and nostrils. He had a history of direct contact with a slaughtered mutton two days ago. He declared controlled diabetes, hypertension, hypertriglyceridemia, and heart failure. Lungs were normal in lung high resolution CT, but multiple lymphadenopathies were seen in the mediastinum. Bilateral axillary lymphadenopathy with a maximum sad of 23 mm and pleural effusion on the right side was observed. CT scan of the nose and sinuses showed an increased density of polyps in the left maxillary sinus. Slides were prepared from the patient's lesions and examined under a light microscope. Bacillus shape with Streptococcus bacteria was seen. Diagnosis: Anthrax co-infection with herpes systemic virus and Streptococcus pyogenes. Interventions: Multidrug therapy started with appropriate antibiotics. Outcomes: The symptoms of the patient gradually disappeared. The patient was discharged without any complications. Lessons: Cutaneous anthrax in endemic areas in patients with skin presentations and a history of contact with infected animals or products should be considered a differential diagnosis. This is more important in mixed infections where the main cause of the problem may be hidden.

Three-Dimensional Assessment of the Pharyngeal Airway in Growing versus Non-Growing Subjects with/without Cleft Lip and Palate

Clefts of the lip or palate (CLPs) are the most common craniofacial birth defect, with a worldwide incidence of ~1 in 700 live births. The objective of this study is to assess the characteristics of the nasopharyngeal airway in growing vs. non-growing cleft lip/palate subjects and compare them with normal subjects. This retrospective study analyzed eighty-seven scans of three groups from cone beam computed tomography (CBCT). The cone beam computed tomography (CBCT) scans were coded and landmarks were identified using a Dolphin three-dimensional (3D) imaging software server (version 11.7; Patterson Dental Supply, Chatsworth, Calif). All values showed strong measurement reliability (&gt;80), except for the nasopharynx measurement. Regarding gender difference, for the nasopharynx, female subjects (1261.32 ± 713.94) showed the lowest significant values in non-growing unilateral compared to males (6496.8 ± 2987) at p = 0.008. For oropharynx, in the growing bilateral cleft group, male subjects (13,046.79 ± 5521.89) showed a significant difference (p = 0.046) compared to females (8468.98 ± 4279.99). MP-SN, B, A, SNA., SN.B., and ANS-ME showed significant differences for cephalometric parameters (p &lt; 0.05). Despite significant differences in linear and angular measurements, volumetric airway measurements showed no significant differences in the growing groups. For non-growing cleft subjects, the cleft anomaly significantly affected the nasal cavity and left maxillary sinus volumes.

Gender Determination from Maxillary Sinus using Computed Tomography Scans - A Radiographic Study.

Purpose of this research was to check the precision of gender identification using computed tomography (CT) head and neck scans and volumetric analysis of the maxillary sinus. For 50 patients (25 females and 25 males), left and right maxillary sinus scans were acquired, and linear measurements (width, length, height, and volume) were assessed. Both maxillary sinus measurements' means and standard deviations were computed and contrasted. Males have been found to have considerably larger maxillary sinuses than females. Accurate gender determination is possible with the use of maxillary sinus.

Sinonasal Non-Intestinal-Type Adenocarcinoma: A Case Report

We report here a 54 year male who presented with a complaint of left sided epistaxis for 5 days &amp; a swelling on the hard palate palate for 8 years. CECT scan revealed a soft tissue lesion involving the hard palate and extending into the left maxillary sinus as well as both nasal cavities. Direct nasal endoscopic biopsy initially suggested an adenocarcinoma not otherwise specified. Immunohistochemistry delineated it as low-grade non-intestinal-type, which occur very uncommonly in the sinonasal region.

AMELOBLASTOMA IN THE POSTERIOR MAXILLA: A CASE REPORT

A 61-year-old male patient presented a painless, well-defined, expansive tumor on the left maxillary edentulous alveolar ridge, which had 18 months of evolution. The lesion measured 30 × 20 mm, had a soft consistency, and was covered by healthy mucosa, though with a localized ulcer. Medical history revealed type II diabetes, hypertension, and pulmonary tuberculosis. Panoramic radiograph showed an unilocular, radiolucent image expanding into the left maxillary sinus, with corticated margins. Cone-beam computed tomography revealed a well-defined, expansive, hypodense image involving the posterior alveolar ridge and extending into the maxillary sinus. Under a clinical hypothesis of mesenchymal neoplasia or fibro-osseous lesion, a puncture was performed, with a negative result. An incisional biopsy was undertaken and the histopathological diagnosis was ameloblastoma. The lesion was resected under general anesthesia, with clear margins. The final diagnosis was conventional (solid) ameloblastoma and the patient has been free of recurrence for 5 months. Support: CAPES. A 61-year-old male patient presented a painless, well-defined, expansive tumor on the left maxillary edentulous alveolar ridge, which had 18 months of evolution. The lesion measured 30 × 20 mm, had a soft consistency, and was covered by healthy mucosa, though with a localized ulcer. Medical history revealed type II diabetes, hypertension, and pulmonary tuberculosis. Panoramic radiograph showed an unilocular, radiolucent image expanding into the left maxillary sinus, with corticated margins. Cone-beam computed tomography revealed a well-defined, expansive, hypodense image involving the posterior alveolar ridge and extending into the maxillary sinus. Under a clinical hypothesis of mesenchymal neoplasia or fibro-osseous lesion, a puncture was performed, with a negative result. An incisional biopsy was undertaken and the histopathological diagnosis was ameloblastoma. The lesion was resected under general anesthesia, with clear margins. The final diagnosis was conventional (solid) ameloblastoma and the patient has been free of recurrence for 5 months. Support: CAPES.

Rhabdomyosarcoma of the Nasal Cavity: A Case Report.

Rhabdomyosarcoma is a high-grade malignant neoplasm with skeletal muscle differentiation; a common soft tissue sarcoma in children but considered one of the rarest in adults. We report a case of 35-year-old male with a chronic productive cough and haemoptysis for five days. A CT scan of the nasopharynx revealed a blocked left maxillary and ethmoid sinus with bone destruction. These findings raised a suspicion of a tumour, and trans-nasal endoscopic sinus surgery was performed. Nasal rhabdomyosarcoma is a rare adult malignant tumour. Most patients have lymphatic metastasis or skull base tumour infiltration at the time of the initial diagnosis and treatment, which poses a challenge to the diagnosis and management. Nasal acinar rhabdomyosarcoma, one of the histopathological types of rhabdomyosarcoma, has rapid disease progression and high mortality. Therefore, the treatment of rhabdomyosarcoma requires a combination of surgery, chemotherapy, radiotherapy, and immunotherapy to work together to achieve the best care for the patient. Nasal acinar rhabdomyosarcoma, one of the histopathological types of rhabdomyosarcoma, has rapid disease progression and high mortality.The survival rate of many adult patients with rhabdomyosarcoma is two years or less.The delay in diagnosis and treatment worsens the already low five-year survival rates in adults.

PRIMORDIAL ODONTOGENIC TUMOR IN A PEDIATRIC PATIENT: RARE CASE REPORT

Primordial Odontogenic Tumor (POT) is a benign lesion of mixed odontogenic origin that mainly affects the posterior mandible of young patients. This report aims to describe a case of POT in a 12-year-old female patient presenting an asymptomatic left facial asymmetry. Intraoral examination showed swelling in the buccal vestibule of the left maxilla. Computed tomography revealed a hypodense, unilocular, and circumscribed lesion associated with an impacted tooth and extending from the left maxillary sinus to the orbital floor. The lesion was enucleated, and the involved tooth were extracted. Microscopically, we observed the proliferation of spindle cells in a fibromyxoid mesenchymal tissue surrounded by columnar odontogenic epithelium. The final diagnosis of POT was established, and the patient has been undergoing a 28-month follow-up with no signs of recurrence. Despite the indolent behavior, it is important to properly diagnose POT in order to avoid invasive surgical approaches. Primordial Odontogenic Tumor (POT) is a benign lesion of mixed odontogenic origin that mainly affects the posterior mandible of young patients. This report aims to describe a case of POT in a 12-year-old female patient presenting an asymptomatic left facial asymmetry. Intraoral examination showed swelling in the buccal vestibule of the left maxilla. Computed tomography revealed a hypodense, unilocular, and circumscribed lesion associated with an impacted tooth and extending from the left maxillary sinus to the orbital floor. The lesion was enucleated, and the involved tooth were extracted. Microscopically, we observed the proliferation of spindle cells in a fibromyxoid mesenchymal tissue surrounded by columnar odontogenic epithelium. The final diagnosis of POT was established, and the patient has been undergoing a 28-month follow-up with no signs of recurrence. Despite the indolent behavior, it is important to properly diagnose POT in order to avoid invasive surgical approaches.

Volumetric Evaluation of Maxillary and Frontal Sinuses in 9–14 year old children — A Cone-Beam Computed Tomography Pilot Study

Context: Literature sums up numerous advantages of volumetric evaluation of maxillary and frontal sinuses in the field of pathology and forensic sciences. However, studies involving paediatric age groups are scarce. Aims and Objectives: To evaluate the volumes of maxillary and frontal sinuses in children aged 9–14 years of age and establish a correlation, if any, between the volumes and the age and sex of the children. Settings and Design: A retrospective study. Materials and Methods: Volumetric measurements of the maxillary and frontal sinuses were conducted on CBCT scans of 30 children aged 9-14 years, divided into three groups, those aged 9–10 years in group A, 11-12 years in group B, and 13-14 years in group C. Statistical Analysis Used: One way ANOVA test to compare the sinus volumes within the groups and unpaired t-test to compare the difference in the volumes in males and females as well as between right and left maxillary sinuses were used. Results: The mean values of the volumes of the right and left maxillary, total maxillary, and frontal sinuses in Group A were 8.4940±1.1966 cm3, 8.3774±1.2047 cm3, 16.8714±2.1212 cm3, and 2.1903±0.8870 cm3; in Group B were 8.7553±0.9067 cm3, 8.3937±1.1461 cm3, 17.1490±1.5732 cm3, and 3.0469±1.5907 cm3; and in Group C were 11.9895±2.230 cm3, 12.6164±1.6797 cm3, 24.6059±4.38536 cm3, and 7.6546±1.7763 cm3, respectively. The difference in the values among all three age groups was statistically significant (p &lt; 0.001). However, there was no significant difference in the values between males and females or between the right and left maxillary sinuses. Conclusion: The study provides volumetric data of maxillary and frontal sinuses in paediatric age groups and proposes a correlation of the volumes with the age of the children.

Letter to the Editor Regarding: “Endoscopic Contralateral Interhemispheric Transfalcine Keyhole Approach for Large Falcine Meningiomas”

A 39-year-old male presented to our institution after sustaining a gunshot wound to the face. He was initially unresponsive with bleeding from the nares bilaterally and was intubated for airway protection. A computed tomography angiogram of the head and neck demonstrated multiple foci of active extravasation in the left maxillary sinus. The patient was taken for emergent neuroendovascular intervention, during which a large, 6.1 mm × 6.4 mm pseudoaneurysm of the left pterygoid artery was discovered and embolized with Onyx liquid embolic agent, with subsequent complete obliteration of the pseudoaneurysm. Embolization immediately halted the bleeding. The patient was neurologically intact at his most recent follow-up appointment. This case demonstrates the importance of obtaining an emergent computed tomography angiography for patients with ballistic facial trauma and early involvement of endovascular neurosurgery for treatment of intractable sinonasal bleeding.

Epithelialization of Free Flap Vascular Pedicles through the Nasal Cavity after Long-term Follow-up: A Case Report

Summary: A 59-year-old man with right maxillary cancer presented with a right buccal fistula and an ectropion of the lower eyelid after multidisciplinary treatment. With no suitable vessels in the right face or neck for anastomosis, we planned reconstruction with a free thinned deep inferior epigastric artery perforator flap using the contralateral left facial artery and vein as the recipient. To simulate the length of the vascular pedicle, we used our original software and determined to use the route passing through the nasal cavity. The vascular pedicle was passed through a tunnel from the medial wall of the right maxillary sinus, through the nasal septum and the medial-frontal wall of the left maxillary sinus, to the left facial artery and vein. The flap survived completely, and facial deformity was corrected. At 1 year postoperatively, there had been concerns about the fragility of the vascular pedicle in the nasal cavity and the possibility of easy bleeding. Endoscopic examination revealed that the vascular pedicle in the nasal cavity was covered by fibrous tissue and multirow lineage epithelium, and an excisional biopsy indicated a low possibility of hemorrhage. Cutting off the vascular pedicle to prevent bleeding may not be necessary because the vascular pedicle through the nasal cavity becomes fibrotic and epithelialized in the surrounding area in the long term.

Do Nasal Anatomical Variations Affect the Maxillary Sinus? A CBCT Volumetric Analysis

Objective: This study aimed to determine the effect of the concha bullosa (CB) and the nasal septum deviation (NSD) on the volume of the maxillary sinuses using ITK-SNAP (http://www.itksnap.org/ download/snap/). Methods: A total of 70 CBCT scans were analyzed. Three groups were evaluated; control (absence of CB), unilateral CB, and bilateral CB. Moreover, scans were classified according to the NSD into control (no deviation), mild, moderate, and severe NSD deviation. The volume of each maxillary sinus was calculated using the ITKSNAP. Intra-observer reliability analysis was performed by paired-sample t-test. Analysis of variance ANOVA and t-test were used to compare the mean bilateral maxillary sinus volumes. Results: Intra-observer reliability for the maxillary sinus volume exhibited no significant difference for both sides (p &gt; 0.05). The mean volume of the right and left maxillary sinuses were 12.98±4.90 cm3 and 13.18±4.99 cm3 , respectively. No significant difference between the volumes of both sides (p &gt; 0.05) was found. The results showed no significant differences between the CB or NSD groups on both sides (p &gt; 0.05). Conclusion: The two anatomical variations have no effect on the maxillary sinus volume. The open-source software ITK-SNAP is a valuable tool for volumetric analysis.

Maxillary Aneurysmal Bone Cyst: About a Case

Introduction: Aneurysmal bone cyst (ABC) is a primary or secondary benign tumor, consisting of an intraosseous cavity, uni or multilocular, with hematic content. It can develop on all bones of the skeleton with, however, a predilection for the long bones and the spine. KOA mainly affects children and young adults, with a slight female predominance. Objective: The aim of this work is to reveal the diagnostic features at the imaging level. Case Report: This is an 11-year-old female patient with no previous pathological history who has presented for 1 year with diffuse maxillofacial pain, with intermittent fluid discharge in the oral cavity. Facial CT scan without and with contrast injection objective a lytic image centered on the lateral wall of the left maxillary sinus bulging into the sinus lumen with a spontaneously hypodense multicompartmental appearance without contrast gain after PDC injection. Conclusion: KAO is a very polymorphic lesion, which presents a diagnostic problem (Aspecific radiological appearance). In spite of the different therapeutic modalities proposed, it is the surgical treatment which exposes less risk of recurrence.

Pseudoaneurysm of the Pterygoid Artery After a Gunshot to the Face

A 39-year-old male presented to our institution after sustaining a gunshot wound to the face. He was initially unresponsive with bleeding from the nares bilaterally and was intubated for airway protection. A computed tomography angiogram of the head and neck demonstrated multiple foci of active extravasation in the left maxillary sinus. The patient was taken for emergent neuroendovascular intervention, during which a large, 6.1 mm× 6.4 mm pseudoaneurysm of the left pterygoid artery was discovered and embolized with Onyx liquid embolic agent, with subsequent complete obliteration of the pseudoaneurysm. Embolization immediately halted the bleeding. The patient was neurologically intact at his most recent follow-up appointment. This case demonstrates the importance of obtaining an emergent computed tomography angiography for patients with ballistic facial trauma and early involvement of endovascular neurosurgery for treatment of intractable sinonasal bleeding.

Low-grade papillary Schneiderian carcinoma with TP53 mutation: a case report and review of the literature

BackgroundLow-grade papillary Schneiderian carcinoma (LGPSC) is a relatively new entity of the sinonasal tract and is characterized by a bland morphology simulating sinonasal papilloma, invasive growth pattern with pushing borders, and aggressive clinical behavior with multiple recurrences and metastatic potential. Recently, DEK::AFF2 fusions were identified in LGPSC. However, some LPGSCs lack DEK::AFF2 fusion, and the molecular features of these tumors have not been clarified.Case presentationA 69-year-old man presented with a discharge of pus from his left cheek. Computed tomography revealed a mass involving the left maxillary sinus, ethmoid sinus, and nasal cavity with the destruction of the orbital wall. The biopsy specimens showed that the tumor had a predominantly exophytic, papillary growth and did not have an apparent stromal invasion. The tumor was composed of multilayered epithelium that showed bland morphology with a round to polygonal shape, abundant eosinophilic cytoplasm, and uniform nuclei. Dense neutrophilic infiltrates were focally present. Immunohistochemically, CK5/6 was strongly and diffusely positive, and p16 was negative. p63 was mainly positive in the basal layer, and EMA was predominantly expressed in the outermost cell layer. DNA-based targeted sequencing showed TP53 R175H mutation, whereas neither EGFR nor KRAS mutation was identified. Reverse transcription polymerase chain reaction and fluorescence in situ hybridization revealed no DEK::AFF2 fusion.ConclusionsWe describe the first case of TP53-mutant LGPSC and review the literature. LGPSC is a genetically heterogeneous entity, and the recognition of this rare entity and comprehensive assessment of clinicopathological and molecular findings are crucial for the correct pathological diagnosis and clinical management.