Superior Ophthalmic Vein Thrombosis: A Case Report in a Previously Healthy Methicillin-Resistant Staphylococcus aureus-Positive Patient.

BACKGROUND Superior ophthalmic vein thrombosis (SOVT) is a rare condition, with an incidence of 3 to 4 cases per million per year. SOVT can be classified according to the underlying etiology into septic or aseptic SOVT. We present a case of right SOVT in a previously healthy patient with a positive blood culture of methicillin-resistant Staphylococcus aureus (MRSA). CASE REPORT A previously healthy 38-year-old female patient presented with a 2-week history of worsening right-sided headache associated with photophobia, phonophobia, right-sided ear pain, and tinnitus. The best corrected visual acuity was 6/12 in the right eye and 6/6 in the left eye. Ophthalmic examination revealed right eye upper lid edema, proptosis, and diplopia in all gazes, mainly vertical. The fundus examination showed a raised hyperemic right optic disc with blurred margins. Laboratory investigations showed a positive blood culture of MRSA and elevated levels of inflammatory markers erythrocyte sedimentation rate and C-reactive protein. Orbital computed tomography examination showed periorbital and orbital cellulitis with superior ophthalmic vein thrombosis. The patient was treated successfully with antibiotics and anticoagulants. At 1-month follow-up, the patient was compliant with medications and reported full resolution of symptoms, with no visual acuity impairment. CONCLUSIONS SOVT is a challenging ophthalmic condition and can be present concurrent with orbital cellulitis or cavernous sinus thrombosis. Early imaging studies and proper management are important to prevent serious complications. Ophthalmologists need to be alerted of the importance of tailoring antibiotics based on the causative agent, to decrease the risk of therapeutic failure and microbial resistance.

Bugs Behind the Bulging Eyeball: Microbiology and Antibiotic Management in Orbital Cellulitis With or Without Subperiosteal Abscess.

The objective of this study is to describe causative pathogens and current antibiotic management among hospitalized children with orbital cellulitis. This retrospective study, performed at a tertiary care children's health system, included patients up to 18 years old who presented with radiographic evidence of orbital cellulitis from 2012 to 2019. Of the 298 patients included in the study, 103 had surgery and an intraoperative culture obtained. A pathogen was recovered in 86 cultures (83.5%). The most common pathogens were Streptococcus anginosus group (26.2%), Streptococcus pyogenes (11.7%), methicillin-susceptible Staphylococcus aureus (10.7%), and Streptococcus pneumoniae (9.7%). Only 8/194 (4.1%) blood cultures returned positive. Median duration of intravenous antibiotics was 4 days and median total duration was 17 days. The most common empiric regimen prescribed was ceftriaxone and clindamycin (64.1%). Despite low incidence of methicillin-resistant S aureus, empiric antibiotics often consisted of 2 antibiotics to ensure coverage for this bacterium.

A rare ocular complication of septicemia: a case series report and literature review.

BACKGROUND: Septicemia that leads to ocular involvement mostly presents as endophthalmitis or panophthalmitis. Contrarily, septicemia without intraocular involvement, known as hematogenous orbital cellulitis (HOC), involves only the orbit and is an extremely rare complication of septicemia and a rare type of orbital cellulitis. CASE PRESENTATION: Four male patients with septicemia presented with orbital involvement without intraocular infection were described in this study. They were 22 (case 1), 15 (case 2), 79 (case 3), and 30 (case 4) years old, with a mean age of 29.75 years. All patients were immunocompromised except for case 2. Cases 1 and 3 had a history of steroid use, whereas case 4 was in a post-chemotherapy myelosuppression phase. Septicemia in case 1 was community-acquired, cases 3 and 4 were hospital-acquired, and case 2 was secondary to acne squeezing. Blood cultures from cases 1, 2, and 3 were positive for Candida albicans, methicillin-resistant Staphylococcus aureus, and Klebsiella pneumoniae, respectively. Case 4 had negative cultures; however, next-generation sequencing reported the presence of Enterococcus faecalis and Rhizopus oryzae. Case 1 had right eye involvement, and both eyes were involved in the other three cases. According to Chandler's classification, case 1 was type 2, case 2 was type 2 (OD) and type 4 (OS), and cases 3 and 4 were type 1 orbital infections. All patients had eyelids erythema, and cases 1 and 2 had mildly decreased visual acuity, proptosis, and painful and restricted ocular motility. Hospital stays ranged from 13 to 43 days (mean, 24 days). All patients received systemic antibiotic therapy based on drug sensitivity and next-generation sequencing results, in combination with multidisciplinary treatment, resulting in complete recovery of ocular and systemic signs and symptoms; no ocular surgical interventions were performed. Extraocular muscle palsy was the last symptom to resolve. CONCLUSION: HOC is predominantly seen in immunocompromised individuals with a high proportion of hospital-acquired infections and positive cultures for pathogens. Infection control using systemic antibiotics targeted at the causative organism guarantees a favorable prognosis.

Abscess volume as a predictor of surgical intervention in children hospitalized with orbital cellulitis: A multicentre cohort study.

IMPORTANCE: Orbital cellulitis with subperiosteal or orbital abscess can result in serious morbidity and mortality in children. Objective volume criterion measurement on cross-sectional imaging is a useful clinical tool to identify patients with abscess who may require surgical drainage. OBJECTIVE: To determine the predictive value of abscess volume and the optimal volume cut-point for surgical intervention. DESIGN: We conducted an observational cohort study using medical records from children hospitalized between 2009 and 2018. SETTING: Multicentre study using data from 6 children's hospitals. PARTICIPANTS: Children were included if they were between 2 months and 18 years of age and hospitalized for an orbital infection with an abscess confirmed on cross-sectional imaging. EXPOSURE: Subperiosteal or orbital abscess volume. MAIN OUTCOME AND MEASURES: The primary outcome was surgical intervention, defined as subperiosteal and/or orbital abscess drainage. Multivariable logistic regression was performed to assess the association of abscess volume with surgery. To determine the optimal abscess volume cut-point, receiver operating characteristic (ROC) analysis was performed using the Youden Index to optimize sensitivity and specificity. RESULTS: Of the 150 participants (mean [SD] age, 8.5 [4.5] years), 68 (45.3%) underwent surgical intervention. On multivariable analysis, larger abscess volume and non-medial abscess location were associated with surgical intervention (abscess volume: adjusted odds ratio [aOR], 1.46; 95% CI, 1.11-1.93; abscess location: aOR, 3.46; 95% CI, 1.4-8.58). ROC analysis demonstrated an optimal abscess volume cut-point of 1.18 mL [AUC: 0.75 (95% CI 0.67-0.83) sensitivity: 66%; specificity: 79%]. CONCLUSIONS AND RELEVANCE: In this multicentre cohort study of 150 children with subperiosteal or orbital abscess, larger abscess volume and non-medial abscess location were significant predictors of surgical intervention. Children with abscesses >1.18 mL should be considered for surgery.

Microbial patterns and culture utility in orbital cellulitis.

PURPOSE: To determine the prevalence and types of pathogens found in children with orbital cellulitis and to evaluate the utility of nonoperative cultures. METHODS: This was a retrospective cohort study of children with imaging-confirmed orbital cellulitis over a period of 8 years. Outcomes included prevalence and types of organisms, polymicrobial infection, mixed aerobic-anaerobic infection, effect of age, and culture utility. RESULTS: Of 220 children with orbital cellulitis, 112 (51%) had cultures taken; 69 (31%) had surgical intervention. Culture sources for the 112 children with cultures included blood (57 patients [51%]), sinus (53 [47%]), orbit (42 [38%]), brain (6 [5%]), and skin/conjunctiva/lacrimal sac (6 [5%]). Streptococcus anginosus group strains grew in cultures from 19 children (17%); methicillin-sensitive Staphylococcus aureus (MSSA), in 15 (13%); Streptococcus pyogenes, in 12 (11%); methicillin-resistant Staphylococcus aureus (MRSA), in 6 (5%); anaerobic/facultative gram negative rods, in 8 (7%); anaerobic Gram-positive cocci, other Viridans group streptococci, and Streptococci pneumoniae, in 3 (3%) each; and normal respiratory/skin flora, in 23 (21%). Polymicrobial infection (P = 0.08) and anaerobic organisms (P = 0.58) did not differ by age (range, 0.1-16.8 years). In all 220 (100%) children, nonoperative cultures were either not obtained (108 [49%]), not helpful in avoiding surgery (69 [31%]), showed no growth (39 [18%]), or grew an organism that did not change management from empiric therapy (4 [2%]). CONCLUSIONS: While many organisms may be cultured from children with orbital cellulitis, Streptococcus and MSSA were the most common in our study cohort. MRSA is uncommon, so initial empiric coverage is not necessary. Rates of polymicrobial and anaerobic infection were similar across ages. Our results indicate that nonoperative cultures are not indicated in the initial medical management of orbital cellulitis; in our cohort, they neither resulted in treatment changes nor helped avoid surgery.

Serologic Evaluations in the Distinction Between Sinusitis-Related Orbital Cellulitis and Periorbital Necrotizing Fasciitis.

PURPOSE: While sinusitis-related orbital cellulitis (SROC) and periorbital necrotizing fasciitis (PNF) share similar clinical presentations, they are managed differently, making rapid recognition of the appropriate clinical entity critical to optimal outcomes. This study was performed to assess whether serologic testing might help clinicians to distinguish between SROC and PNF. METHODS: A retrospective review analysis was used to compare initial complete blood counts and comprehensive metabolic panels among adult patients with SROC and PNF. Statistical evaluations were used to determine the significance of differences between the groups. RESULTS: Thirteen patients with PNF and 14 patients with SROC were identified. The 2 groups were similar in age, gender, and likelihood of immunosuppression ( p > 0.05 for each metric). Mean leukocyte counts were 18.52 (standard deviation = 7.02) and 10.31 (standard deviation = 5.77) for PNF and SROC, respectively ( p = 0.0057). White blood cell levels were above normal limits for 12 patients with PNF (92.3%) and 7 patients with SROC (50%) ( p = 0.017). No other laboratory test was significantly different between the 2 groups. CONCLUSIONS: While the majority of serologic testing was quite similar in patients with either SROC or PNF, leukocyte levels may represent an important clue to distinguish between the two diseases. Clinical evaluation remains the gold standard to make the proper diagnosis, but markedly elevated white blood cell counts should prompt clinicians to at least consider a diagnosis of PNF.

Evaluation of mild periorbital cellulitis and home-based therapy in children-EPOCH study: A prospective single centre cohort study.

BACKGROUND: Paediatric periorbital cellulitis is a common eye condition and warrants prompt management for the prevention of complications. International consensus on the approach to optimal management of children with mild periorbital cellulitis including ambulatory management is lacking. We aimed to prospectively investigate the safety and effectiveness of ambulatory management of children with mild periorbital cellulitis. METHODS: Over a 23-month period, we prospectively enrolled 70 children aged between 2 and 16 years who presented to the emergency department with mild periorbital cellulitis. Demographic and clinical data were collected. Eligible children were commenced on oral antibiotics and were discharged home with close outpatient ambulatory care and ophthalmology follow up. We used descriptive statistics for data presentation. RESULTS: Of the 70 children with mild periorbital cellulitis, 30 (43%) had unknown aetiology. Sixty-five (92%) children received a structured ambulatory follow up. Five children (7%) received inpatient parenteral antibiotics for worsening of local symptoms within 24 h of initial presentation. One child developed orbital cellulitis at follow up. There was no mortality or significant morbidity noted in this group and none of the children needed surgical intervention. CONCLUSIONS: Ambulatory care for children with mild periorbital cellulitis is an effective and safe management strategy. This might prevent hospitalisation, reduce the burden on hospital bed occupancy and promote patient care in the community.

Seasonal variations, acute rhinosinusitis and orbital infections in children.

BACKGROUND: Orbital infections in children are commonly secondary to acute bacterial rhinosinusitis (ABRS). It is unclear whether seasonal variations can predispose to these complications mirroring acute rhinosinusitis incidence. OBJECTIVE: To determine the incidence of ABRS as a cause of orbital infections and whether seasonality is a risk factor. METHODS: A retrospective review of all children who presented to West Virginia University children's hospital between 2012 and 2022 were reviewed. All children with CT evidence of orbital infection were included. Date of occurrence, age, gender, and presence of sinusitis were reviewed. Children with orbital infection secondary to tumors, trauma, or surgery were excluded. RESULTS: 118 patients were identified with mean age of 7.3 years with 65 (55.1 %) males. 66 (55.9 %) children had concomitant sinusitis on CT scan, and the distribution of orbital complications per season showed 37 (31.4 %) cases occurred in the winter season, followed by 42 (35.6 %) cases in spring, 24 (20.3 %) cases in summer, and 15 (12.7 %) in fall. Children with orbital infections during winter & spring had sinusitis in 62 % of children vs. 33 % in other seasons (P = 0.02). Preseptal cellulitis was present in 79 (67 %) children, 39 (33 %) children with orbital cellulitis, and 40 (33.9 %) children with abscesses. 77.6 % children were treated with IV antibiotics and 94 % with oral antibiotics, and 14 (11.9 %) with systemic steroids. Only 18 (15.3 %) children required surgery. CONCLUSIONS: There seems to be a seasonal predisposition for orbital complications mainly in the winter and spring seasons. Rhinosinusitis was present in 55.6 % of children presenting with orbital infections.

Microbiology and Antibiotic Resistance Profiles of Orbital Subperiosteal Abscesses: A Comparison of Pediatric, Adolescent, and Adult Populations.

PURPOSE: The purpose of this study was to compare the microbiology and antibiotic resistance profiles of orbital subperiosteal abscesses (SPA) among 3 age cohorts. METHODS: A retrospective study was conducted at a tertiary care center through a medical record search to identify patients with orbital cellulitis and SPA on imaging from January 1, 2000 to September 10, 2022. Patients were categorized into pediatric (<9 years old), adolescent (9-18 years old), and adult (>18 years old) cohorts. Primary outcomes included culture and antibiotic susceptibility results. Secondary outcomes included antibiotic therapy and surgical intervention. RESULTS: Of the 153 SPA patients included, 62 (40.5%) were in the pediatric cohort (4 months-8 years, mean 5.0 ± 2.7), 51 (33.3%) were adolescent (9-18 years, 12.7 ± 2.8), and 40 (26.1%) were adult (19-95, 51.8 ± 19.3). Viridians group Streptococci were the most frequent organisms isolated across groups. The anaerobic infection rate was higher in the adult compared to the pediatric group (23.0% vs, 4.0%, p = 0.017), while that of the adolescent did not differ significantly from either. Pediatric patients carried a lower rate of clindamycin resistance than adolescent and adult cohorts, who shared similar rates (0 vs. 27.0% and 28.0%, respectively; p = 0.016). There were progressive increases in duration of intravenous antibiotic therapy ( p < 0.195) and rate of surgical intervention ( p < 0.001) going from younger to older cohorts. CONCLUSION: Organisms isolated from orbital SPA from the past 2 decades demonstrate a predominance of Streptococcal species. Older age may be associated with anaerobic infection, clindamycin resistance, and more aggressive management. Adolescent infections are more similar to adult rather than pediatric counterparts but may require less aggressive management than the former.

Recent advancements in nanotechnology-based bacteriophage delivery strategies against bacterial ocular infections.

Antibiotic resistance is growing as a critical challenge in a variety of disease conditions including ocular infections leading to disastrous effects on the human eyes. Staphylococcus aureus (S. aureus) mediated ocular infections are very common affecting different parts of the eye viz. vitreous chamber, conjunctiva, cornea, anterior and posterior chambers, tear duct, and eyelids. Blepharitis, dacryocystitis, conjunctivitis, keratitis, endophthalmitis, and orbital cellulitis are some of the commonly known ocular infections caused by S. aureus. Some of these infections are so fatal that they could cause bilateral blindness like panophthalmitis and orbital cellulitis, which is caused by methicillin-resistant S. aureus (MRSA) and vancomycin-resistance S. aureus (VRSA). The treatment of S. aureus infections with known antibiotics is becoming gradually difficult because of the development of resistance against multiple antibiotics. Apart from the different combinations and formulation strategies, bacteriophage therapy is growing as an effective alternative to treat such infections. Although the superiority of bacteriophage therapy is well established, yet physical factors (high temperatures, acidic pH, UV-rays, and ionic strength) and pharmaceutical barriers (poor stability, low in-vivo retention, controlled and targeted delivery, immune system neutralization, etc.) have the greatest influence on the viability of phage virions (also phage proteins). A variety of Nanotechnology based formulations such as polymeric nanoparticles, liposomes, dendrimers, nanoemulsions, and nanofibres have been recently reported to overcome the above-mentioned obstacles. In this review, we have compiled all these recent reports and discussed bacteriophage-based nanoformulations techniques for the successful treatment of ocular infections caused by multidrug-resistant S. aureus and other bacteria.

Methicillin-resistant Staphylococcus aureus-associated orbital cellulitis: a case series.

PURPOSE: In recent years, methicillin-resistant Staphylococcus aureus (MRSA) orbital cellulitis (OC) has drawn increasing clinical and public health concern. We present a case series of MRSA OC encountered at four Australian tertiary institutions. METHODS: A multi-centre retrospective case series investigating MRSA OC in Australia from 2013 to 2022. Patients of all ages were included. RESULTS: Nine cases of culture-positive non-multi-resistant MRSA (nmMRSA) OC were identified at four tertiary institutions across Australia (7 male, 2 female). Mean age was 17.1 ± 16.7 years (range 13-days to 53-years), of which one was 13 days old, and all were immunocompetent. Eight (88.9%) patients had paranasal sinus disease, and seven (77.8%) had a subperiosteal abscess. Four (44.4%) had intracranial extension, including one (11.1%) case which was also complicated by superior sagittal sinus thrombosis. Empirical antibiotics, such as intravenous (IV) cefotaxime alone or IV ceftriaxone and flucloxacillin, were commenced. Following identification of nmMRSA, targeted therapy consisting of vancomycin and/or clindamycin was added. Nine (100%) patients underwent surgical intervention. Average hospital admission was 13.7 ± 6.9 days (range 3-25 days), with two patients requiring intensive care unit (ICU) admission due to complications related to their orbital infection. All patients had favourable prognosis, with preserved visual acuity and extraocular movements, following an average follow-up period of 4.6 months (range 2-9 months). CONCLUSION: NMMRSA OC can follow an aggressive clinical course causing severe orbital and intracranial complications across a wide demographic. However, early recognition, initiation of targeted antibiotics and surgical intervention when required can effectively manage these complications and achieve favourable visual outcomes.

Variation in the Management of Hospitalized Children With Orbital Cellulitis Over 10 Years.

OBJECTIVES: No previous study has examined the management of hospitalized children with orbital cellulitis at both children's and community hospitals across multiple sites in Canada. We describe variation and trends over time in diagnostic testing and imaging, adjunctive agents, empiric antibiotics, and surgical intervention in children hospitalized with orbital cellulitis. PATIENTS AND METHODS: Multicenter cohort study of 1579 children aged 2 months to 18 years with orbital cellulitis infections admitted to 10 hospitals from 2009 to 2018. We assessed hospital-level variation in the use of diagnostic tests, imaging, antibiotics, adjunctive agents, surgical intervention, and clinical outcomes using X2, Mann-Whitney U, and Kruskal-Wallis tests. The association between clinical management and length of stay was evaluated with median regression analysis with hospital as a fixed effect. RESULTS: There were significant differences between children's hospitals in usage of C-reactive protein tests (P < .001), computed tomography scans (P = .004), MRI scans (P = .003), intranasal decongestants (P < .001), intranasal corticosteroids (P < .001), intranasal saline spray (P < .001), and systemic corticosteroids (P < .001). Children's hospital patients had significantly longer length of hospital stay compared with community hospitals (P = .001). After adjustment, diagnostic testing, imaging, and subspecialty consults were associated with longer median length of hospital stay at children's hospitals. From 2009 to 2018, C-reactive protein test usage increased from 28.8% to 73.5% (P < .001), whereas erythrocyte sedimentation rate decreased from 31.5% to 14.1% (P < .001). CONCLUSIONS: There was significant variation in diagnostic test usage and treatments, and increases in test usage and medical intervention rates over time despite minimal changes in surgical interventions and length of stay.

Methicillin-Resistant Staphylococcus aureus Sepsis and Orbital Cellulitis Leading to a Combined Central Retinal Artery and Vein Occlusion: A Case Report.

Combined central retinal artery and vein occlusion (CCRAVO) is a rare entity characterized by features of tortuous retinal veins, retinal hemorrhage, optic disk edema and pallor, macula edema, cherry-red spot, and cotton-wool spots. The occurrence of CCRAVO in the adult population is often in the setting of systemic disease; while CCRAVO in the pediatric population is frequently associated with infection of the sinuses, preseptal cellulitis, or orbital cellulitis. It has been hypothesized that CCRAVO can result from methicillin-resistant Staphylococcus aureus (MRSA) sepsis-induced coagulation disturbances, orbital cellulitis, and even orbital compartment syndrome; however, there are insufficient reports of this complication. This case report sheds light on one such case with irreversible vision loss as a sequela.

Pediatric Orbital Cellulitis/Abscess: Microbiology and Pattern of Antibiotic Prescribing.

INTRODUCTION: The treatment for pediatric orbital cellulitis/abscess is trending towards intravenous antibiotic management alone in appropriate cases. Without cultures to guide therapy, knowing the local microbiology is of utmost importance in managing these patients. METHODS: We conducted a retrospective case series for patients age 2 months to 17 years, who were hospitalized between January 1, 2013, and December 31, 2019, to evaluate the local microbiology and pattern of antibiotic prescribing in pediatric orbital cellulitis. RESULTS AND DISCUSSION: Of 95 total patients, 69 (73%) received intravenous antibiotics only and 26 (27%) received intravenous antibiotics plus surgery. The most common organism cultured was Streptococcus anginosus, followed by Staphylococcus aureus, and group A streptococcus. Methicillin-resistant Staphylococcus aureus (MRSA) prevalence was 9%. MRSA-active antibiotics remain the most frequently used antibiotics.

The Role of Steroids for Pediatric Orbital Cellulitis - Review of the Controversy.

Orbital cellulitis in the pediatric population is treated primarily with antibiotic therapy. This leaves the inflammatory component unchecked. Corticosteroid therapy has been used to accelerate recovery and decrease the long-term morbidity in other infectious conditions. Its use has also been proposed for pediatric orbital cellulitis. The aim of this manuscript is to conduct a literature review to summarize existing evidence and understand ongoing controversies. Overall, prior investigations on corticosteroid therapy for pediatric orbital cellulitis are limited by their study design and sample sizes. One of the most discussed potential benefits is that adjuvant steroid therapy for pediatric orbital cellulitis is associated with shorter hospitalization without major infectious complications. However, decreased hospitalization length is an imperfect metric, especially without standardized criteria for hospital discharge. Future studies are warranted to better guide the use of adjuvant steroid therapy and to optimize its potential in the management of pediatric orbital cellulitis.

Microbiology of bacterial orbital cellulitis-tertiary institutional experiences in South Australia: a multi-centre retrospective study.

PURPOSE: This study describes the microbiology of bacterial orbital cellulitis (OC) over an 11-year period and its clinical associations at three tertiary institutions in Adelaide, South Australia. METHODS: Multi-centre retrospective study of the microbiology of bacterial OC between January 2012 and August 2022. Pre-septal cellulitis was excluded. Differences in means were determined by the Independent Samples t-test, and categorical data was analysed via Pearson's Chi square. A P-value < 0.05 was statistically significant. RESULTS: 99 patients (male: 69, mean age: 22.0 ± 23.8 years old), of which 70.7% were aged ≤ 18 years. Sinus and orbital abscess cultures had the greatest positive yield (73.7%). Frequency of organisms: Streptococcus species (34.3%), Staphylococcus aureus (28.3%), Haemophilus species (5.1%), mixed anaerobes (3.0%), Enterobacter cloacae (2.0%), Moraxella catarrhalis (1.0%), Pseudomonas aeruginosa (1.0%), Corynebacterium species (1.0%), Klebsiella pneumoniae (1.0%), Proteus mirabilis (1.0%), Citrobacter koseri (1.0%), and Enterococcus species (1.0%). Streptococcus species predominated in the paediatric population, with a statistically significant difference in mean age between Streptococcus species and Staphylococcus aureus (14.1 ± 16.5 vs 27.6 ± 24.6 years old, respectively) (P = 0.028). No organism was cultured in 32.3% of cases. Methicillin-resistant Staphylococcus aureus (MRSA) accounted for 28.6% of all Staphylococcus aureus isolates, with 50% occurring between 2021 and 2022. CONCLUSION: Yearly microbiological trends have remained largely constant in South Australia. The causative organism was not identified in 32.3% of cases, further emphasising appropriate empirical antibiotics, and obtaining microbiology from various sources. MRSA OC remains of increased clinical and public health concern and may be associated with a more aggressive disease course.