Assessing neophyte response to daily disposable silicone hydrogel contact lenses: A randomised clinical trial investigation over one month.

OBJECTIVE: This randomised clinical trial assessed the impact on symptoms, tear film dynamics and ocular surface integrity of daily disposable silicone-hydrogel contact lenses (CLs) over a month, paying special attention to lid wiper epitheliopathy (LWE) and its implications for CL discomfort. METHODS: Neophyte CL wearers (n = 44, 21.09 ± 5.00 years old) were randomly assigned to either the experimental (n = 24) or control group (n = 20). Participants assigned to the experimental group were required to wear daily disposable CLs for 1 month for at least 8 h/day and 6 days/week. All participants were healthy subjects (no history of ocular surgery or active ocular disease) with spherical refractive errors between -8.00 and +5.00 D and cylindrical power <0.75 D. At the baseline and 1-month sessions, the Dry Eye Questionnaire 5 (DEQ-5) was completed, together with the measurement of tear film osmolarity with the TearLab osmometer, tear meniscus height (TMH) and lipid layer pattern (LLP) using a slit-lamp with Tearscope Plus attached, fluorescein break-up time (FBUT), maximum blink interval (MBI), corneal staining with fluorescein under cobalt blue light and LWE with lissamine green under slit lamp and halogen white light. RESULTS: At the baseline session, LWE showed a negative correlation with DEQ-5 (r = -0.37, p = 0.02). Significant differences in FBUT and LWE (p = 0.04) and a positive correlation between LWE and DEQ-5 (r = 0.49, p = 0.007) were observed at 1 month. Intrasession analysis at 1 month showed significant differences between the experimental and control groups in DEQ-5, FBUT and LWE (all p ≤ 0.02). Intersession analysis in the experimental group showed variations in DEQ-5, FBUT and LWE (all p ≤ 0.02) but no significant variation in the control group (all p ≥ 0.11). CONCLUSION: The presence of LWE was significantly correlated with higher symptom values in the DEQ-5. Also, participants in the experimental group presented higher values of LWE after 1 month of CL wear, in comparison with the control group.

First-in-human Clinical Trial of a Novel Eyelid warming Device in Meibomian Gland Dysfunction.

BACKGROUND: Meibomian gland dysfunction (MGD) causes significant patient morbidity as well as economic burden. OBJECTIVES: To evaluate a novel eyelid warming and a neuro-stimulating device that delivers heat via low-level infrared radiation to the eyelids of patients with MGD. METHODS: In this prospective interventional study, patients with MGD were recruited at a single medical center. The main outcome measures included changes in tear break-up time (TBUT), Schirmer's test, and Ocular Surface Disease Index (OSDI), overall satisfaction, and corneal signs of dry eye. Patients were instructed to use the device twice daily for 5 minutes on each eye for a total of 14 days. Follow-up assessments were performed after the 2-week treatment. RESULTS: A total of 10 patients were included; mean age was 67 ± 16 years; six males (60%). Changes in pre- vs. post-treatment TBUT (5.0-6.11), OSDI (28.1-23.9), and Schirmer score (8.67-7.11) were not statistically significant. Over a course of 243 treatments, 131 (54%) demonstrated improvement in symptoms, 40% found no change, and 6% experienced worsening of symptoms. General satisfaction was observed overall in 80% of the patients. No adverse events were observed. CONCLUSIONS: In this first study of a novel eyelid warming device, overall subjective satisfaction was reported in 80% of patients. Potential advantages of this user-friendly device include its ability to improve MGD and tear film stability, as well as symptomatic relief, while allowing the user to continue with normal daily functioning while undergoing treatment.

Floppy eyelid syndrome and obstructive sleep apnea: a unique phenotype?

INTRODUCTION: Floppy eyelid syndrome (FES) is an underdiagnosed condition stereotypically found in obese, middle-aged men, characterized by a lax eyelid tarsus which readily everts without excess mechanical manipulation. Obstructive sleep apnoea (OSA) is the most frequently reported comorbidity in patients suffering from FES. The aim of this study was to determine whether or not individuals with FES present with distinct anthropometric characteristics in comparison to patients without FES suspected of having OSA. METHODS: A retrospective case-control study in which FES patients and controls all referred for investigation of suspected OSA, matched for sex, ethnicity, residential location, age (± 2 years), date of sleep study (± 1 month), and type of sleep study were compared for anthropometric, comorbidity, and sleep data differences. RESULTS: OSA prevalence and severity, assessed by apnoea-hypopnea index (AHI), revealed no significant differences between patients with FES (n = 39) and those without (n = 75), (85% vs 88%, p = 0.91 and 31.9 ± 28.7 vs 28.5 ± 16.6, p = 0.81 respectively), despite patients with FES being more obese (p = 0.02). Patients with FES had significantly lower Epworth sleepiness scale (ESS) scores after treatment with CPAP (5.3 ± 4.1 vs 9.4 ± 5.0, p = 0.028). Patients with FES exhibited increased prevalence of hernias (15% vs 4%, p = 0.032), dermatological (41% vs 17%, p = 0.006) and rheumatological (15% vs 3%, p = 0.012) comorbidities. CONCLUSION: FES patients appear to exhibit a distinct phenotype with increased prevalence of comorbidities related to matrix metalloproteinase dysfunction and significant improvement of daytime hypersomnolence with continuous positive airway pressure (CPAP) treatment.

Efficacy and Safety evaluation of a single thermal pulsation system treatment (Lipiflow®) on meibomian gland dysfunction: a randomized controlled clinical trial.

PURPOSE: Evaluate the efficacy and safety of LipiFlow® thermal pulsation treatment system compared with lid massage combined warm compress in Chinese patients with meibomian gland dysfunction (MGD). METHODS: Patients (n = 100 eyes, 50 subjects) diagnosed with MGD were recruited for this prospective, randomized, 3-month clinical trial. In Lipiflow group, patients (n = 50 eyes) received a single LipiFlow® thermal pulsation system treatment. In warm compress group, patients (n = 50 eyes) underwent warm compress daily for two weeks after an initial manual lid massage. Patients' symptoms were evaluated using Standard Patient Evaluation for Eye Dryness (SPEED) questionnaire. Safety parameters included best-corrected visual acuity (BCVA), intraocular pressure (IOP) and objective parameters including meibomian glands yielding lipid secretion (MGYLS) number, meibomian glands secretion (MGS) score, lipid layer thickness (LLT), tear-film breakup time (TBUT), corneal fluorescein staining (CFS) were measured and presented from baseline and to 3 months post-treatment. RESULTS: Baseline parameters in both groups were comparable (p > 0.05). SPEED score and TBUT improved in two groups from baseline to 3 months. MGYLS number, MGS score, LLT improved in LipiFlow group and these improvements were maintained with no significant regression at 3 months. CFS showed significant improvement in warm compress group at 1 month compared with LipiFlow group. Moreover, the correlation analysis indicated LLT was positively correlated with TBUT, MGS score, and MGYLS number. CONCLUSION: A single 12-min LipiFlow treatment is an effective therapy for MGD patients and can achieve improvements in symptoms alleviation and meibomian gland lipid secretion function lasting for at least 3 months.

[Chinese expert consensus on meibomian gland dysfunction: definition and classification (2023)].

Meibomian gland dysfunction (MGD) is a common clinical ocular surface disease. In recent years, great progress has been made in basic and clinical research on MGD, and new diagnostic and therapeutic methods have been continuously applied to clinical practice. To improve the understanding of MGD among Chinese ophthalmologists and standardize the diagnosis and treatment of MGD, the Chinese Branch of the Asia Dry Eye Society and relevant academic groups organized experts to discuss the definition and classification of MGD based on recent research progress and clinical experience at home and abroad, forming consensus opinions for the reference of clinicians.

[Chinese expert consensus on meibomian gland dysfunction: diagnosis and management (2023)].

Meibomian gland dysfunction (MGD) is a common ocular surface disease. In recent years, the meibomian gland-related examination and treatment technologies have evolved rapidly. In order to further optimize the diagnostic process of MGD in China and improve the treatment efficiency of MGD, the Chinese Branch of the Asian Dry Eye Society has organized relevant experts to discuss the clinical characteristics of MGD in China and the progress of research at home and abroad. Based on the expert consensus formed in 2017, the updated consensus opinions have been developed for clinical physicians to refer to in the diagnosis and management of MGD.

Effect of intense pulsed light using acne filter on eyelid margin telangiectasia in moderate-to-severe meibomian gland dysfunction.

Evaluate the improvement in clinical signs and symptoms in patients with moderate-to-severe meibomian gland dysfunction (MGD) treated with intense pulsed light (IPL) using an acne filter. A retrospective chart review of 70 eyes of 35 patients with moderate-to-severe MGD treated with IPL using the acne filter was performed. IPL treatment was administered using the acne filter four times at 2- to 3-week intervals to upper and lower eyelids. We evaluated tear break-up time (TBUT), matrix metalloproteinase (MMP)-9, Sjögren's International Clinical Collaborative Alliance (SICCA) staining score, and Oxford staining grade. We performed Schirmer's test I without topical anesthesia, slit-lamp microscopic examination of lid margin and meibomian gland, and patient's symptom score assessment and evaluated the incidence of adverse effects in the ocular and periocular areas at baseline and 30 days after the final treatment. Significant improvements (P < 0.001) were observed in TBUT, SICCA staining score, Oxford staining grade, quality of meibum, consistency of meibum, lid margin telangiectasia, MGD grade, and patient's symptom scores after acne filter IPL treatment. Furthermore, the positivity (100 to 71.43%, P = 0.002) and level (2.43 ± 0.98 to 1.14 ± 0.78, P < 0.001) of MMP-9 significantly decreased after treatment. However, there was no significant improvement in Schirmer's test I (P = 0.224). No systemic or regional adverse effects were observed in any patient. IPL treatment using the acne filter is an effective and safe therapeutic modality for treating moderate-to-severe MGD, especially for lid margin telangiectasia and MMP-9.

New strategies for the management of ocular surface disease in glaucoma patients.

PURPOSE OF REVIEW: Glaucoma patients commonly suffer from ocular surface disease (OSD). As treatment strategies, medications and devices for the treatment of OSD as well as glaucoma surgical approaches evolve rapidly, it is important to consider their application to these patients. RECENT FINDINGS: OSD in glaucoma patients may lead to reduced reliability of diagnostic tests, decreased medication compliance, poor surgical outcomes, and overall decreased quality of life. Chronic use of topical glaucoma medications has been linked to the development of limbal stem cell deficiency, and the role of preservatives in OSD continues to be demonstrated. Preservative free glaucoma medications as well as new anti-inflammatory agents for the treatment of OSD are now available. Omega-3 fatty acid supplementation and punctal plugs have been shown to benefit glaucoma patients with OSD. Drop burden may be reduced through the use of the new sustained-release delivery systems, selective laser trabeculoplasty, and minimally invasive glaucoma surgery. SUMMARY: There are multiple emerging strategies for managing OSD that may be applied to patients with glaucoma. With continued research and clinical experiences, we hope to better understand the multifaceted relationship between glaucoma and OSD and develop evidence-based algorithms for the management of these complex patients.

A Single-center Retrospective Trial of a Blink-assisted Eyelid Device in Treating the Signs and Symptoms of Dry Eye.

SIGNIFICANCE: The clinical features of meibomian gland disease include altered tear film stability, damage to the ocular surface, symptoms of ocular surface irritation, and visual fluctuations. Finding an adequate treatment to alleviate a patient's signs and symptoms is vital to caring for those with dry eye disease resulting from meibomian gland disease. PURPOSE: The purpose of this analysis was to determine whether the controlled heating of meibomian glands with the SmartLid devices (TearCare) combined with evacuation of the liquefied meibum using a handheld clearance assistant would improve a patient's dry eye symptoms (as measured by the Standardized Patient Evaluation of Eye Dryness [SPEED] questionnaire) and signs (as measured by meibomian gland expression [MGE] scores). METHODS: This study involved a retrospective analysis of data gathered in a single-center ophthalmology/optometry practice. The symptom frequency and severity were assessed using the SPEED questionnaire, and the signs were assessed via MGE scores before and after (8 to 12 weeks) treatment. A further analysis evaluating efficacy in subgroups based on age, race, and sex was performed. A statistical analysis was performed with t tests for group comparisons. RESULTS: A SPEED questionnaire was answered by 92 patients with dry eye disease. In addition, each patient's meibomian gland function was recorded as MGE scores for each eye (176 eyes). These procedures were completed before and approximately 8 weeks after a single bilateral TearCare treatment. The median total SPEED score was reduced from 16 to 9, and the total MGE scores improved from 5.0 to 9.0 in the right eye and 4.0 to 9.0 in the left eye after a single TearCare treatment. CONCLUSIONS: A single TearCare treatment was effective in reducing both the signs and symptoms of dry eye in all subjects.

Effect of IPL in Patients with Meibomian Gland Dysfunction.

PURPOSE: To evaluate the effect of IPL (intense pulsed light) treatment in patients with meibomian gland dysfunction (MGD). METHODS: Clinical data of 25 patients with MGD who underwent IPL treatment at the department of ophthalmology of Ludwig-Maximilians-University between 2016 and 2018 were analyzed. Demographics, clinical history, examination findings (eyelid vascularization, meibomian gland findings, conjunctival redness, tear film break-up time [TFBUT], corneal staining (Oxford grading scale [OGS]), and subjective patients' findings (including ocular surface disease index [OSDI]) were collected from each visit (D1, D15, D45, D75). RESULTS: All included patients underwent three sessions of IPL treatment in both eyes (D1, D15, D45). There was a significant improvement after IPL treatment (D75) in TFBUT (p < 0.001), corneal staining (OGS) (p < 0.001), conjunctival redness (p < 0.001), lid margin edema (p < 0.001) and redness (p < 0.001), meibum quality (p < 0.001), lid margin telangiectasia (p = 0.005), meibomian gland obstruction (p = 0.001), and OSDI score (p = 0.004). Even after the first IPL session, significant improvements in TFBUT (p < 0.001), corneal staining (OGS p < 0.001), conjunctival redness (p < 0.022), lid margin edema (p < 0.001) and redness (p < 0.016), meibum quality (p = 0.014), and OSDI score (p < 0.013) were noted. There were no relevant negative side effects. Subgroup analysis for age, sex, duration or severity of disease, and associated diagnosis of rosacea showed no significant difference in effectiveness. CONCLUSION: IPL is an effective and safe treatment for patients with MGD, which can be used as a supportive therapeutic option.

[Modern approaches to the treatment of meibomian gland dysfunction]. / Sovremennye podkhody k lecheniyu disfunktsii meibomievykh zhelez.

The eyelids are a delicate and complex dynamic structure with primary function to protect the eye surface. The term «meibomian gland dysfunction¼ (MGD) first appeared in the mid-1980s. This lesion is known to result in a disturbance of the tear film, eye irritation symptoms, clinically significant inflammation and diseases of the eye surface. The progression of MGD leads to hyperosmolarity of the tear film, its instability, an increase in the bacterial load of the eyelid margin, blepharitis and generalized inflammation of the ocular surface. For patients who require surgical treatment, a healthy eyelid is very important. Despite postoperative functional recovery, most of these patients experience dry eye syndrome (DES), which can lead to symptoms of eye irritation and deterioration of visual acuity due to instability of the tear film. In the early stages of MGD, it is advisable to begin treatment with a conversation about correct frequent blinking, rest during visual activity, adequate water intake, and a specific diet. Later, patients are advised to use an ultrasonic air humidifier, warm dry compresses, practice proper eyelid hygiene and perform massages, apply preservative-free lubricants, azithromycin, omega-3 preparations, and undergo local anti-inflammatory therapy. In case of a tick-borne infestation, the International Expert Group recommends the use of scrubs with 50% tea tree oil for treating the eyelids. In order to achieve a long-term effect or permanent remission, it is necessary to practice daily eyelid hygiene with the help of gels, special napkins and shampoos over a long period of time. Correctly selected medical treatment in accordance with the stage of the disease supplemented with massages and warm dry compresses lead to a significant improvement in the quality of life of patients with MGD and DES. The simplicity of eyelid hygiene is currently ensured by the availability of tools specially designed for the safe treatment of its edges, which have a complex histological and anatomical structure.

Sinus pericranii in the upper eyelid: diagnosis and management guidelines.

Sinus pericranii (SP) is a rare malformation involving aberrant connections between the dural venous sinuses and extracranial veins. Classically considered congenital pathology, there are reported instances of post-traumatic SP in adults. Very rarely, the upper eyelid is involved and the resulting ptosis can obstruct the visual axis. In these cases, surgical removal may be warranted. Because of the high risk of massive intraoperative hemorrhage, careful preoperative identification and diagnostic workup is essential. The authors report a patient with new onset, asymmetric eyelid ptosis referred for evaluation, and subsequently diagnosed with SP. Through a multi-disciplinary assessment, deferring surgical intervention was determined to be appropriate management. The lesion was monitored clinically, and at 6 months follow-up, there were no noted adverse outcomes.

Subgaleal haematoma as a cause of periorbital necrotising fasciitis: a case report.

Subgaleal haematoma in adulthood and periorbital necrotising fasciitis are unusual occurrences that have not been reported together. We discuss the first observed case of a 35-year-old female with periorbital necrotising fasciitis postulated to be caused by subgaleal haematoma following head trauma that was successfully managed with antibiotics and surgery.

Eyelid abscess masking underlying sebaceous cell carcinoma.

Sebaceous cell carcinoma is well known as the "great masquerader" mimicking other benign or malignant eyelid conditions and lesions. We present a case of a middle age male presenting with a subacute left upper lid abscess who was ultimately diagnosed with malignant sebaceous cell carcinoma after incision and drainage and treatment with broad spectrum antibiotics. This case highlights the deceptive clinical and radiographic appearance of this tumor and the importance of histologic examination in atypical or refractory periorbital abscesses.

Comparison of two intense pulsed light patterns for treating patients with meibomian gland dysfunction.

PURPOSE: The objective of this was to determine the efficacy of different patterns of intense pulsed light (IPL) therapy in patients with meibomian gland dysfunction (MGD). MATERIALS AND METHOD: IPL treatment was administered in 124 eyes of 62 patients with MGD-associated dry eye disease (DED). These patients were divided randomly into two groups treated with different IPL patterns. The first group was treated with "Optimal Pulse Technology" (OPT) (n = 29) and received three consecutive treatments (10-14 J/cm2) with three weeks between treatments. The other group was treated with "Intense Regulated Pulsed Light" (IRPL) (n = 33) and received four treatments (9-13 J/cm2) on days (D)1, D15, D45, and D75. The Ocular Surface Disease Index (OSDI), fluorescein breakup time (FTBUT), first and the average of noninvasive keratograph tear breakup times (NIKBUT), Schirmer I tests, conjunctival hyperemia, corneal fluorescent staining (CFS), tear meniscus height (TMH), MG secretion, and dropout were examined before each treatment and at one and three months after treatment. RESULTS: Compared to baseline, the clinical symptoms and signs in both groups were significantly improved at one and three months after IPL treatment. However, compared to the IRPL group, the OPT-treated group showed significant improvement in the clarity of MG secretions (P = 0.001), the number of MGs yielding clear or cloudy liquid secretions (P < 0.001), the total MG secretion score (P < 0.001) in lower eyelid, the lid margin score in upper (P < 0.001) and lower eyelids (P = 0.013), the first NIKBUT (P = 0.009), and FTBUT (P = 0.006). CONCLUSIONS: These results suggest that IPL has significant clinical value in treating patients with MGD. OPT IPL treatment was more effective in improving MG function in lower eyelids and partial tear film signs than IRPL IPL treatment. TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov, and the clinical trial accession number is NCT02481167.

Efficacy of wheat hot pack (dry heat) and pottery hot pack (moist heat) on eyelid temperature and tissue blood flow in healthy eyes: a randomized control trial.

PURPOSE: To investigate the eyelid temperature (Temp) and tissue blood flow (TBF) changes in healthy eyes using wheat hot pack (WHP) and pottery hot pack (PHP). METHODS: A randomized, double-blind, within-subject crossover study design was conducted in a Thai tertiary care center. All healthy subjects received warm compress treatment with WHP and PHP. The subjects were randomized to receive the WHP or the PHP at the first sequence. Temp and TBF measurements were taken at baseline, and every 2 min during the 10-min application of the heated compresses, and every 2 min for a 10-min duration after the compresses were removed. RESULTS: There were 29 females (96.7%) and 1 male. The mean (SD) age of the subjects was 33.17 (5.21) years. Two warm compresses were able to increase the surface lid Temp significantly from the baseline Temp at every time point of measurement and location. For the WHP application, the maximum surface Temp (SD) of the outer upper lid, outer lower lid, and inner lower lid were 40.07 (0.80) °C, 38.44 (0.91) °C, and 35.83 (0.71) °C, respectively (all P value < 0.001) and under the PHP application, the highest surface Temp (SD) were 40.63 (0.97) °C, 38.32 (1.27) °C, and 35.82 (0.71) °C, respectively (all P value < 0.001). Both WHP and PHP were able to increase TBF significantly with no adverse events and these effects can be sustained until 20 min. CONCLUSIONS: The results of this study suggest the potential of using these warm compresses for meibomian gland dysfunction. Further clinical research is needed.

Advances in dry eye disease treatment.

PURPOSE OF REVIEW: The prevalence and burden of dry eye disease continues to grow at a rapid pace, creating an increased need for new therapies. In a sector once limited to only a handful of treatments, clinicians now have multiple options available for patients who fail traditional therapies. This review summarizes the various treatment options available to clinicians treating complex dry eye disease patients. RECENT FINDINGS: As we better understand the multifactorial mechanisms leading to dry eye disease, treatments increasingly focus on the amelioration of the underlying deficiencies and inflammation, rather than on transient symptomatic relief alone. Most topical medications seek to replace deficient growth factors and/or decrease inflammation on the ocular surface. The majority of new devices and procedures seek to treat meibomian gland dysfunction, with one new device stimulating tear production through utilizing the nasolacrimal reflex pathway. SUMMARY: Clinicians have more options at their disposal in the treatment of dry eye disease than ever before, including topical medications and devices.

Efficacy of Plate Expression of Meibum on Tear Function and Ocular Surface Findings in Meibomian Gland Disease.

PURPOSE: To evaluate the clinical effectiveness of expression treatment on meibomian gland disease (MGD). METHODS: Seventeen right eyes of 17 patients with MGD were divided into 3 groups in this randomized prospective clinical study: no expression group: routine treatment with no expression (five patients, five eyes); digital expression group: routine treatment with digital expression (five patients, five eyes); and plate expression group: routine treatment with plate expression (seven patients, seven eyes). All groups received the same routine treatment for 1 month. Tear film break-up time (TBUT), vital staining scores, meibum expressibility, and the dry eye-related quality of life score (DEQS) questionnaire results were assessed before and 1 month after treatment. RESULTS: There was a statistically significant difference of posttreatment TBUT among groups as determined by one-way analysis of variance (P<0.05). A post hoc test revealed that TBUT was statistically significantly higher in plate expression group compared with digital expression group. The fluorescein staining score did not show a statistically significant difference among the groups. Meibum expressibility and the DEQS scores improved in all groups. CONCLUSION: Plate expression when used as an adjunct to routine medical management of MGD has been found to be a comparatively effective treatment in terms of improvement of tear film stability compared with no expression or digital expression.

Update on the association between dry eye disease and meibomian gland dysfunction.

Dry eye disease is one of the most common ophthalmic complaints; it results from the activity of various pathways and is considered a multifactorial disease. An important factor that contributes to the onset of dry eye disease is meibomian gland dysfunction. Meibomian gland dysfunction causes a disruption in the tear film lipid layer which affects the rate of tear evaporation. This evaporation leads to tear hyperosmolarity, eventually triggering the onset of dry eye disease. Dry eye disease and meibomian gland dysfunction are strongly associated with each other, such that many of their risk factors, signs, and symptoms overlap. This review aimed to provide an update on the association between dry eye disease and meibomian gland dysfunction. A stepwise approach for diagnosis and management is summarised.

[Emerging strategies for the treatment of Meibomian gland dysfunction].

Meibomian gland dysfunction (MGD), as a chronic,diffuse Meibomian gland disease,is one of the most common ophthalmological clinical diseases. Symptoms can be mild,such as ocular discomfort, but severe cases resulting in ocular surface damage could affect patients' visual function. Moreover,with the absence of a thorough examination of eyelid status and Meibomian gland prior to ocular surface surgery, it could cause severe postoperative complications. As a usual but easily overlooked disease, MGD and its associated ocular surface diseases have drawn greater attention,on the other hand,some emerging therapies,in addition to the clinically recognized treatments, provided doctors with more effective treatments at their disposal,and plenty of research achievements have been published. This article emphasizes on new physical approaches in the treatments of MGD and its associated ocular surface diseases. (Chin J Ophthalmol, 2019,55:465-468).