Multiple Sclerosis Clinic Utilization is Associated with Fewer Emergency Department Visits.

OBJECTIVE: Alberta is a Canadian province with a high prevalence of multiple sclerosis (MS). In this ecological study, we examined group differences in health care utilization among persons with MS (pwMS) living within different regions of the province. METHODS: pwMS were identified from provincial administrative databases spanning 2002-2011. Utilization of health care services was determined for a 2-year period (April 2010-March 2012). Residential postal codes placed patients into their provincial health care zones. As data were provided to the investigators in an aggregated form, tests of statistical significance and confounding were not performed. RESULTS: In total, 11,721 pwMS were identified. During the 2-year observation period, 96.2% of pwMS accessed a family physician and 57.1% accessed a neurologist. Nearly all (99.0%) pwMS who received neurologist care in Calgary visited an MS clinic, in contrast to Edmonton where a larger proportion (34.8%) received solely community neurologist care. More pwMS living in Edmonton accessed the ED (41.1%) compared to Calgary (35.7%), and the rate of visits per pwMS was higher in Edmonton (1.07/pwMS) than in Calgary (0.81/pwMS). The frequency of inpatient admissions was similar. CONCLUSIONS: Over 2 years, most pwMS accessed primary care and over half saw a neurologist. Despite a similar frequency of inpatient admissions, the frequency of ED visits by pwMS was higher in Edmonton compared to Calgary, where more patients received MS clinic care. Although this exploratory study is subject to several limitations, our findings suggest that specialized MS clinics may reduce costly ED visits.

The Prevalence and Incidence of Dementia with Lewy Bodies: a Systematic Review.

BACKGROUND: Population-based prevalence and incidence studies are essential for understanding the societal burden of dementia with Lewy bodies (DLB). METHODS: The MEDLINE and EMBASE databases were searched to identify publications addressing the incidence and/or prevalence of DLB. References of included articles and prior systematic reviews were searched for additional studies. Two reviewers screened all abstracts and full-text reviews, abstracted data and performed quality assessments. RESULTS: Twenty-two studies were included. Incidence rates ranged from 0.5 to 1.6 per 1000 person-years. DLB accounted for 3.2-7.1% of all dementia cases in the incidence studies. Point and period prevalence estimates ranged from 0.02 to 63.5 per 1000 persons. Increasing prevalence estimates were reported with increasing age. DLB accounted for from 0.3 to 24.4% of all cases of dementia in the prevalence studies. CONCLUSIONS: DLB becomes more common with increasing age and accounts for about 5% of all dementia cases in older populations.

The Prevalence and Incidence of Frontotemporal Dementia: a Systematic Review.

BACKGROUND: Population-based prevalence and incidence studies are essential for understanding the burden of frontotemporal dementia (FTD). METHODS: The MEDLINE and EMBASE databases were searched to identify population-based publications from 1985 to 2012, addressing the incidence and/or prevalence of FTD. References of included articles and prior systematic reviews were searched for additional studies. Two reviewers screened all abstracts and full-text reviews, abstracted data and performed quality assessments. RESULTS: Twenty-six studies were included. Methodological limitations led to wide ranges in the estimates for prevalence (point prevalence 0.01-4.6 per 1000 persons; period prevalence 0.16-31.04 per 1000 persons) and incidence (0.0-0.3 per 1000 person-years). FTD accounted for an average of 2.7% (range 0-9.1%) of all dementia cases among prevalence studies that included subjects 65 and older compared to 10.2% (range 2.8-15.7%) in studies restricted to those aged less than 65. The cumulative numbers of male (373 [52.5%]) and female (338 [47.5%]) cases from studies reporting this information were nearly equal (p=0.18). The behavioural variant FTD (bvFTD) was almost four times as common as the primary progressive aphasias. CONCLUSIONS: Population-based estimates for the epidemiology of FTD varied widely in the included studies. Refinements in the diagnostic process, possibly by the use of validated biomarkers or limiting case ascertainment to specialty services, are needed to obtain more precise estimates of the prevalence and incidence of FTD.

The Prevalence and Incidence of Dementia: a Systematic Review and Meta-analysis.

UNLABELLED: Introduction Dementia is a common neurological condition affecting many older individuals that leads to a loss of independence, diminished quality of life, premature mortality, caregiver burden and high levels of healthcare utilization and cost. This is an updated systematic review and meta-analysis of the worldwide prevalence and incidence of dementia. METHODS: The MEDLINE and EMBASE databases were searched for relevant studies published between 2000 (1985 for Canadian papers) and July of 2012. Papers selected for full-text review were included in the systematic review if they provided an original population-based estimate for the incidence and/or prevalence of dementia. The reference lists of included articles were also searched for additional studies. Two individuals independently performed abstract and full-text review, data extraction, and quality assessment of the papers. Random-effects models and/or meta-regression were used to generate pooled estimates by age, sex, setting (i.e., community, institution, both), diagnostic criteria utilized, location (i.e., continent) and year of data collection. RESULTS: Of 16,066 abstracts screened, 707 articles were selected for full-text review. A total of 160 studies met the inclusion criteria. Among individuals 60 and over residing in the community, the pooled point and annual period prevalence estimates of dementia were 48.62 (CI95%: 41.98-56.32) and 69.07 (CI95%: 52.36-91.11) per 1000 persons, respectively. The respective pooled incidence rate (same age and setting) was 17.18 (CI95%: 13.90-21.23) per 1000 person-years, while the annual incidence proportion was 52.85 (CI95%: 33.08-84.42) per 1,000 persons. Increasing participant age was associated with a higher dementia prevalence and incidence. Annual period prevalence was higher in North America than in South America, Europe and Asia (in order of decreasing period prevalence) and higher in institutional compared to community and combined settings. Sex, diagnostic criteria (except for incidence proportion) and year of data collection were not associated with statistically significant different estimates of prevalence or incidence, though estimates were consistently higher for females than males. CONCLUSIONS: Dementia is a common neurological condition in older individuals. Significant gaps in knowledge about its epidemiology were identified, particularly with regard to the incidence of dementia in low- and middle-income countries. Accurate estimates of prevalence and incidence of dementia are needed to plan for the health and social services that will be required to deal with an aging population.

The Prevalence and Incidence of Dementia Due to Alzheimer's Disease: a Systematic Review and Meta-Analysis.

BACKGROUND: Updated information on the epidemiology of dementia due to Alzheimer's disease (AD) is needed to ensure that adequate resources are available to meet current and future healthcare needs. We conducted a systematic review and meta-analysis of the incidence and prevalence of AD. METHODS: The MEDLINE and EMBASE databases were searched from 1985 to 2012, as well as the reference lists of selected articles. Included articles had to provide an original population-based estimate for the incidence and/or prevalence of AD. Two individuals independently performed abstract and full-text reviews, data extraction and quality assessments. Random-effects models were employed to generate pooled estimates stratified by age, sex, diagnostic criteria, location (i.e., continent) and time (i.e., when the study was done). RESULTS: Of 16,066 abstracts screened, 707 articles were selected for full-text review. A total of 119 studies met the inclusion criteria. In community settings, the overall point prevalence of dementia due to AD among individuals 60+ was 40.2 per 1000 persons (CI95%: 29.1-55.6), and pooled annual period prevalence was 30.4 per 1000 persons (CI95%: 15.6-59.1). In community settings, the overall pooled annual incidence proportion of dementia due to AD among individuals 60+ was 34.1 per 1000 persons (CI95%: 16.4-70.9), and the incidence rate was 15.8 per 1000 person-years (CI95%: 12.9-19.4). Estimates varied significantly with age, diagnostic criteria used and location (i.e., continent). CONCLUSIONS: The burden of AD dementia is substantial. Significant gaps in our understanding of its epidemiology were identified, even in a high-income country such as Canada. Future studies should assess the impact of using such newer clinical diagnostic criteria for AD dementia such as those of the National Institute on Aging-Alzheimer's Association and/or incorporate validated biomarkers to confirm the presence of Alzheimer pathology to produce more precise estimates of the global burden of AD.

Health-related behaviors and comorbidities in people with epilepsy: Changes in the past decade.

OBJECTIVE: We aimed to explore the patterns of health-related behaviors (HRBs) such as smoking and physical activity in people with epilepsy in the community and examine whether behaviors have changed over the past decade. METHODS: We conducted a repeated cross-sectional study using data from a series of five cycles (2001-2011) of the Canadian Community Health Survey, a national population-based survey. The proportions and odds ratios with 95% confidence intervals for HRBs and comorbidities in people with epilepsy (PWE) compared to respondents without epilepsy were calculated for each survey over the 10-year period, and estimates were examined for changes over time. RESULTS: The study included 522,722 participants of whom 3,220 (0.6%) had epilepsy. The proportion of PWE who did not participate in physical activity decreased over time (2001 = 17.2%, 2010/2011 = 8.5%), as did the proportion of PWE who smoked cigarettes (2001 = 32.3%, 2010/2011 = 18.0%). PWE had consistently reduced alcohol consumption in comparison to the general population. Fewer than half of participants met the recommended daily guidelines for fruit and vegetable consumption. An apparent reduction in the prevalence of heart disease occurred in PWE (2001 = 11.7%, 2010/2011 = 4.0%), but not in people without epilepsy; however, similar trends were not observed for other cardiovascular comorbidities studied. SIGNIFICANCE: Apparent improvements in smoking cessation and physical activity occurred in PWE. Despite these improvements, physicians should continue to counsel their patients on the importance of healthy lifestyle choices. Further exploration into the reasons for the apparent decrease in the prevalence of heart disease in PWE is warranted.

Highlights from the 6th Annual University of Calgary Leaders in Medicine Research Symposium and the Keynote Address by Dr. Danuta Skowronski.

The Leaders in Medicine (LIM) Program at the University of Calgary hosted its 6th Annual Research Symposium on November 14, 2014, showcasing the quality and breadth of work performed by students at the Cumming School of Medicine. Participation at this year's event was our most successful to date, with a total of six oral and 77 poster presentations during the afternoon symposium. For a detailed description of the work presented at the symposium, please see the Proceedings from the 6th Annual University of Calgary Leaders in Medicine Research Symposium published in this issue of Clinical and Investigative Medicine.

Proceedings from the 6th Annual University of Calgary Leaders in Medicine Research Symposium.

On November 14, 2014, the Leaders in Medicine (LIM) program at the Cumming School of Medicine, University of Calgary hosted its 6th Annual Research Symposium. Dr. Danuta Skowronski, Epidemiology Lead for Influenza and Emerging Respiratory Pathogens at the British Columbia Centre for Disease Control (BCCDC), was the keynote speaker and presented a lecture entitled "Rapid response research during emerging public health crises: influenza and reflections from the five year anniversary of the 2009 pandemic". The LIM symposium provides a forum for both LIM and non-LIM medical students to present their research work, either as an oral or poster presentation. There were a total of six oral presentations and 77 posters presented. The oral presentations included: Swathi Damaraju, "The role of cell communication and 3D Cell-Matrix environment in a stem cell-based tissue engineering strategy for bone repair"; Menglin Yang, "The proteolytic activity of Nepenthes pitcher fluid as a therapeutic for the treatment of celiac disease"; Amelia Kellar, "Monitoring pediatric inflammatory bowel disease - a retrospective analysis of transabdominal ultrasound"; Monica M. Faria-Crowder, "The design and application of a molecular profiling strategy to identify polymicrobial acute sepsis infections"; Waleed Rahmani, "Hair follicle dermal stem cells regenerate the dermal sheath, repopulate the dermal papilla and modulate hair type"; and, Laura Palmer, "A novel role for amyloid beta protein during hypoxia/ischemia". The article on the University of Calgary Leaders in Medicine Program, "A Prescription that Addresses the Decline of Basic Science Education in Medical School," in a previous issue of CIM (2014 37(5):E292) provides more details on the program. Briefly, the LIM Research Symposium has the following objectives: (1) to showcase the impressive variety of projects undertaken by students in the LIM Program as well as University of Calgary medical students; (2) to encourage medical student participation in research and special projects; and, (3) to inform students and faculty about the diversity of opportunities available for research and special projects during medical school and beyond.The following abstracts were submitted for publication.

A prescription that addresses the decline of basic science education in medical school.

Over 30 years ago a cry rang out through the proverbial halls of academia; "The clinician scientist is an endangered species." These prophetic words have been reverberated in the ears of every specialty and every general medical organization in deafening tones. Why is the role of the clinician scientist or clinician investigator so important that this phrase has been repeated subsequently in medical and educational journals? Simply put, the clinician scientist bridges the ravine between the ever-growing mountain of scientific knowledge and the demanding patient centered clinical care. Here, we describe the current educational model established by the University of Calgary, Leaders in Medicine Program. Our program seeks to train future physicians and clinician scientists by incorporating training in basic science, translational and clinical research with clinical and medical education in a longitudinal program to students of traditional MD/PhD, MD/MSc or MD/MBA stream as well as interested Doctor of Medicine students.

Patient perceptions and barriers to epilepsy surgery: evaluation in a large health region.

PURPOSE: Despite evidence that carefully selected patients with refractory focal epilepsy benefit from epilepsy surgery, significant delays remain. We examined patient knowledge and perceptions regarding epilepsy surgery. METHODS: A 5-minute questionnaire was administered to consecutive adults with focal epilepsy seen in the epilepsy clinic in a large Canadian health region. Survey items assessed the following: (1) knowledge of surgical options, (2) perceptions about the risks of surgery vs. ongoing seizures, (3) disease disability, (4) treatment goals, and (5) demographic and socioeconomic variables. Patient responses were compiled to calculate a "Barriers to Epilepsy Surgery Composite" (BESC) score. RESULTS: Of 129 eligible patients, 107 completed the questionnaire (response rate: 83%). The average BESC score was 60/100. Apprehension about epilepsy surgery was less likely among patients who had previously undergone epilepsy surgery and those born in Canada. DISCUSSION: People with epilepsy often have hindering perceptions that can contribute to delays in surgical care.

Sensitivity and specificity of alternative screening methods for systematic reviews using text mining tools.

OBJECTIVES: To evaluate the impact of text mining (TM) on the sensitivity and specificity of title and abstract screening strategies for systematic reviews (SRs). STUDY DESIGN AND SETTING: Twenty reviewers each evaluated a 500-citation set. We compared five screening methods: conventional double screen (CDS), single screen, double screen with TM, combined double screen and single screen with TM, and single screen with TM. Rayyan, Abstrackr, and SWIFT-Review were used for each TM method. The results of a published SR were used as the reference standard. RESULTS: The mean sensitivity and specificity achieved by CDS were 97.0% (95% confidence interval [CI]: 94.7, 99.3) and 95.0% (95% CI: 93.0, 97.1). When compared with single screen, CDS provided a greater sensitivity without a decrease in specificity. Rayyan, Abstrackr, and SWIFT-Review identified all relevant studies. Specificity was often higher for TM-assisted methods than that for CDS, although with mean differences of only one-to-two percentage points. For every 500 citations not requiring manual screening, 216 minutes (95% CI: 169, 264) could be saved. CONCLUSION: TM-assisted screening methods resulted in similar sensitivity and modestly improved specificity as compared to CDS. The time saved with TM makes this a promising new tool for SR.

Patient knowledge about issues related to pregnancy in epilepsy: a cross-sectional study.

In 2009, new guidelines were established by the American Academy of Neurology regarding pregnancy in women with epilepsy. A questionnaire was developed to assess patient knowledge of current guidelines related to epilepsy and pregnancy. Patients were recruited from a single outpatient clinic in a large Canadian tertiary care center. Patients were eligible to participate if they were female, of reproductive age, had active epilepsy for at least 6 months and were not cognitively impaired. One hundred women completed the survey (response rate 87%) with a median score of 40%. A significant association was found between total score and years of education (p<0.001). Significant associations were not found between total score and epilepsy duration (p=0.37), previously being pregnant (p=0.22), and polytherapy (p=0.31). Patient knowledge of the impact of epilepsy on pregnancy is low. More knowledge translation efforts are required to increase knowledge of issues related to pregnancy for women with epilepsy.

Using a standardized assessment tool to measure patient experience on a seizure monitoring unit compared to a general neurology unit.

Seizure monitoring unit (SMU) research typically focuses on diagnostic utility and medical management of epilepsy. However, patient safety and satisfaction are also imperative to high-quality SMU care. This study uses a standardized tool to evaluate patient experience on a SMU compared to a general neurology unit (GNU). The 27-item Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey was telephone-administered post-discharge to a sample of patients from our SMU and GNU. Data from a 33-month period were reviewed, encompassing 217 SMU patient admissions and 317 GNU patient admissions. On average, SMU patients were 14.7 years younger and stayed in the hospital 4.2 days longer than GNU patients. SMU patients provided lower overall mental health ratings (p<.001), perceived nursing staff to be more responsive to the call button (p<.001), and assigned higher overall ratings to their stay (p<0.05). Lower education was associated with more favorable hospital ratings on both units (p<0.05).

Pearls & Oy-sters: Cerebral Abscess Secondary to Pulmonary Arteriovenous Malformation in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant condition that is linked to a myriad of neurologic complications arising from vascular malformations of the brain, spinal cord, and lungs. Our case describes a previously healthy 3-year-old male who presented to hospital with fever of unknown origin and was found to have a brain abscess stemming from a pulmonary arteriovenous malformation (PAVM). This etiology was identified after a period of diagnostic delay; the medical team was suspicious for a proximal embolic source due to the presence of multiple tiny infarcts seen on MRI of the brain, but transthoracic echocardiogram and head and neck angiogram were unremarkable. Fortunately, an enhanced CT of the chest was performed, identifying a moderately sized PAVM. PAVMs are associated with intracranial abscesses due to shunting and loss of the normal filtering effects of the lung capillary bed. Impaired pulmonary filtration can permit paradoxical thromboemboli and septic microemboli to enter systemic circulation, predisposing patients with PAVMs to cerebral abscess and ischemic stroke. Screening for PAVMs with contrast-enhanced echocardiogram or enhanced CT of the chest may be considered in patients with cryptogenic brain abscess or recurrent embolic stroke of unknown origin. PAVMs are often associated with hereditary hemorrhagic telangiectasia (HHT). As many features of HHT have delayed clinical manifestation, genetic testing for HHT should be considered in all people with PAVM, even in the absence of other clinical features. In our case, genetic testing returned positive, confirming a new diagnosis of HHT type 1.

Neurologists' and neurology residents' knowledge of issues related to pregnancy for women with epilepsy.

We aimed to assess physician knowledge for 2009 guidelines established by the American Academy of Neurology and American Epilepsy Society regarding issues related to pregnancy for women with epilepsy. A questionnaire was developed and distributed to all neurologists and neurology residents practicing in a large Canadian health region serving a population of 1.4 million. Descriptive statistics were obtained and percentage of correct responses was calculated. Forty-five physicians completed the survey (response rate = 83.3%), with a median correct score of 50%. Residents were more likely (93.3%) to state that this information was important to their practice than staff physicians (40.0%). Overall knowledge of outcomes associated with specific AEDs was poor; less than half of the physicians correctly indicated which AEDs were associated with adverse outcomes for the majority of drug-related questions. We recommend multifaceted, interactive implementation strategies for increasing knowledge of guideline contents.

Twice Negative PCR in a Patient With Herpes Simplex Virus Type 1 (HSV-1) Encephalitis.

Untreated herpes simplex virus type 1 (HSV-1) encephalitis is associated with high mortality. Missed cases can have devastating consequences. Detection of HSV-1 in cerebrospinal fluid (CSF) with polymerase chain reaction (PCR) is reported to have high sensitivity and specificity and is considered the diagnostic gold standard for HSV-1 encephalitis. In this article, we report a case of autopsy-confirmed HSV-1 encephalitis where CSF PCR returned negative on 2 occasions. A 64-year-old man presented with fever, left-sided weakness, and altered level of consciousness. Magnetic resonance imaging demonstrated right mesial temporal lobe diffusion restriction and electroencephalography showed right lateralized periodic discharges. Lumbar puncture was performed on day 1 for which CSF PCR returned negative for HSV-1. Empiric antiviral and antibiotic treatments were continued due to high clinical suspicion of HSV-1 encephalitis. Repeat lumbar puncture on day 5 was unchanged and empiric treatments were discontinued. On day 13, he developed status epilepticus requiring intensive care unit admission. A third CSF sample returned positive for HSV-1. Acyclovir was restarted but he continued to clinically worsen and supportive care was withdrawn. Autopsy confirmed widespread HSV-1 meningoencephalitis. Negative CSF PCR should be interpreted with caution in cases where there is high clinical suspicion of HSV-1 encephalitis. Current guidelines suggest repeating CSF HSV-1 PCR within 3 to 7 days in suspicious cases while continuing empiric therapy. However, missed cases can occur even with repeated testing. Empiric treatment with acyclovir should be considered in cases with high clinical suspicion of HSV-1 encephalitis, while investigations for alternate treatable diagnoses are continued.

Health status, health related behaviours and chronic health indicators in people with Tourette Syndrome: A Canadian population-based study.

Tourette Syndrome (TS) is a childhood onset neuropsychiatric disorder. The objective of this study was to compare self-perceived health status, health-related behaviours, and chronic health conditions in individuals with and without TS using population-based data. Data were derived from Canadian Community Health Survey (CCHS) 2010 and 2011 cycles. The CCHS is a national population-based cross-sectional survey that collects information related to health status for Canadians. We evaluated the association between TS and self-perceived health, health related behaviours and chronic health conditions. 122,884 Canadians participated with 122 participants diagnosed with TS. After controlling for age and sex, the TS population was significantly less likely to have good self-perceived physical health and significantly more likely to need help with instrumental activities of daily living. More individuals with TS were diagnosed with an anxiety disorder, a mood disorder, or asthma. We observed no significant differences in health related behaviours between individuals with TS and the general population other than a higher odds of consultation for mental health. Individuals with TS experience a higher frequency of anxiety and mood disorders, and require more assistance with activities of daily living than the general population.

Neurologists' knowledge of and attitudes toward epilepsy surgery: a national survey.

OBJECTIVES: In the current study, we aim to assess potential neurologist-related barriers to epilepsy surgery among Canadian neurologists. METHODS: A 29-item, pilot-tested questionnaire was mailed to all neurologists registered to practice in Canada. Survey items included the following: (1) type of medical practice, (2) perceptions of surgical risks and benefits, (3) knowledge of existing practice guidelines, and (4) barriers to surgery for patients with epilepsy. Neurologists who did not complete the questionnaire after the initial mailing were contacted a second time by e-mail, fax, or telephone. After this reminder, the survey was mailed a second time to any remaining nonresponders. RESULTS: In total, 425 of 796 neurologists returned the questionnaire (response rate 53.5%). Respondents included 327 neurologists who followed patients with epilepsy in their practice. More than half (56.6%) of neurologists required patients to be drug-resistant and to have at least one seizure per year before considering surgery, and nearly half (48.6%) failed to correctly define drug-resistant epilepsy. More than 75% of neurologists identified inadequate health care resources as the greatest barrier to surgery for patients with epilepsy. CONCLUSIONS: A substantial proportion of Canadian neurologists are unaware of recommended standards of practice for epilepsy surgery. Access also appears to be a significant barrier to epilepsy surgery and surgical evaluation. As a result, we are concerned that patients with epilepsy are receiving inadequate care. A greater emphasis must be placed on knowledge dissemination and ensuring that the infrastructure and personnel are in place to allow patients to have timely access to this evidence-based treatment.

Feasibility of using an online tool to assess appropriateness for an epilepsy surgery evaluation.

OBJECTIVES: To examine the applicability of applying an online tool to determine the appropriateness of referral for an epilepsy surgical evaluation and to determine whether appropriateness scores are concordant with the clinical judgment of epilepsy specialists. METHODS: We prospectively applied the tool in 107 consecutive patients with focal epilepsy seen in an epilepsy outpatient clinic. Variables collected included seizure type, epilepsy duration, seizure frequency, seizure severity, number of antiepileptic drugs (AEDs) tried, AED-related side effects, and the results of investigations. Appropriateness ratings were then compared with retrospectively collected information concerning whether a surgical evaluation had been considered. RESULTS: Thirty-nine patients (36.4%) were rated as appropriate for an epilepsy surgical evaluation, all of whom had adequately tried 2 or more appropriate AEDs. The majority of patients (84.6%) rated as appropriate had previously been considered or referred for an epilepsy surgical evaluation. Tool feasibility of use was high, with the exception of assessing whether previous AED trials had been adequate and discrepancies between physician and patient reports of AED side effects. CONCLUSIONS: Our evidence-based, online clinical decision tool is easily applied and able to determine whether patients with focal epilepsy are appropriate for a surgical evaluation. Future validation of this tool will require application in clinical practice and assessment of potential improvements in patient outcomes.