Implementing stroke care in a lower-middle-income country: results and recommendations based on an implementation study within the Nepal Stroke Project.

Background: Globally, the majority of strokes affect people residing in lower- and lower-middle-income countries (LMICs), but translating evidence-based knowledge into clinical practice in regions with limited healthcare resources remains challenging. As an LMIC in South Asia, stroke care has remained a healthcare problem previously unaddressed at a national scale in Nepal. The Nepal Stroke Project (NSP) aims to improve acute stroke care in the tertiary healthcare sector of Nepal. We hereby describe the methods applied and analyze the barriers and facilitators of the NSP after 18 months. Methods: The NSP follows a four-tier strategy: (1) quality improvement by training healthcare professionals in tertiary care centers; (2) implementation of in-hospital stroke surveillance and quality monitoring system; (3) raising public awareness of strokes; and (4) collaborating with political stakeholders to facilitate public funding for stroke care. We performed a qualitative, iterative analysis of observational data to analyze the output indicators and identify best practices. Results: Both offline and online initiatives were undertaken to address quality improvement and public awareness. More than 1,000 healthcare professionals across nine tertiary care hospitals attended 26 stroke-related workshops conducted by Nepalese and international stroke experts. Monthly webinars were organized, and chat groups were made for better networking and cross-institutional case sharing. Social media-based public awareness campaigns reached more than 3 million individuals. Moreover, live events and other mass media campaigns were instituted. For quality monitoring, the Registry of Stroke Care Quality (RES-Q) was introduced. Collaboration with stakeholders (both national and international) has been initiated. Discussion: We identified six actions that may support the development of tertiary care centers into essential stroke centers in a resource-limited setting. We believe that our experiences will contribute to the body of knowledge on translating evidence into practice in LMICs, although the impact of our results must be verified with process indicators of stroke care.

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge.

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions.

Stroke epidemiology and outcomes of stroke patients in Nepal: a systematic review and meta-analysis.

BACKGROUND: With an increasing burden of stroke, it is essential to minimize the incidence of stroke and improve stroke care by emphasizing areas that bring out the maximum impact. The care situation remains unclear in the absence of a national stroke care registry and a lack of structured hospital-based data monitoring. We conducted this systematic review and meta-analysis to assess the status of stroke care in Nepal and identify areas that need dedicated improvement in stroke care. METHODS: A systematic literature review was conducted to identify all studies on stroke epidemiology or stroke care published between 2000 and 2020 in Nepal. Data analysis was done with Statistical Package for Social Sciences (SPSS) and Comprehensive Meta-analysis (CMA-3). RESULTS: We identified 2533 studies after database searching, and 55 were included in quantitative and narrative synthesis. All analyses were done in tertiary care settings in densely populated central parts of Nepal. Ischemic stroke was more frequent (70.87%) than hemorrhagic (26.79%), and the mean age of stroke patients was 62,9 years. Mortality occurred in 16.9% (13-21.7%), thrombolysis was performed in 2.39% of patients, and no studies described thrombectomy or stroke unit care. CONCLUSION: The provision of stroke care in Nepal needs to catch up to international standards, and our systematic review demonstrated the need to improve access to quality stroke care. Dedicated studies on establishing stroke care units, prevention, rehabilitation, and studies on lower levels of care or remote regions are required.

Are digital social media campaigns the key to raise stroke awareness in low-and middle-income countries? A study of feasibility and cost-effectiveness in Nepal.

BACKGROUND: Stroke is a major global health problem and was the second leading cause of death worldwide in 2020. However, the lack of public stroke awareness especially in low- and middle-income countries (LMICs) such as Nepal severely hinders the effective provision of stroke care. Efficient and cost-effective strategies to raise stroke awareness in LMICs are still lacking. This study aims to (a) explore the feasibility of a social media-based stroke awareness campaign in Nepal using a cost-benefit analysis and (b) identify best practices for social media health education campaigns. METHODS: We performed a stroke awareness campaign over a period of 6 months as part of a Stroke Project in Nepal on four social media platforms (Facebook, Instagram, Twitter, TikTok) with organic traffic and paid advertisements. Adapted material based on the World Stroke Day Campaign and specifically created videos for TikTok were used. Performance of the campaign was analyzed with established quantitative social media metrics (impressions, reach, engagement, costs). RESULTS: Campaign posts were displayed 7.5 million times to users in Nepal. 2.5 million individual social media users in Nepal were exposed to the campaign on average three times, which equals 8.6% of Nepal's total population. Of those, 250,000 users actively engaged with the posts. Paid advertisement on Facebook and Instagram proved to be more effective in terms of reach and cost than organic traffic. The total campaign cost was low with a "Cost to reach 1,000 users" of 0.24 EUR and a "Cost Per Click" of 0.01 EUR. DISCUSSION: Social media-based campaigns using paid advertisement provide a feasible and, compared to classical mass medias, a very cost-effective approach to inform large parts of the population about stroke awareness in LMICs. Future research needs to further analyze the impact of social media campaigns on stroke knowledge.

Venture of a Tertiary Care Neurosurgical Center in Course of COVID-19 Lockdown without RT-PCR.

"I will not permit considerations of age, disease or disability, creed, ethnic origin, gender, nationality, political affiliation, race, sexual orientation, social standing or any other factor to intervene between my duty and my patient." Obliged by the aforementioned oath, no medical practitioner shall sit in a moral judgment on any patient but will treat their illness to the best of their ability whatever the circumstances. A clear concord was yet to be authorized after the World Health Organization (WHO) declared the global pandemic of severe acute respiratory syndrome coronavirus 2infection. As a diagnostic modality, WHO recommended real-time reverse transcription-polymerase chain reaction (RT-PCR) as a reliable test; however, its availability in a deprived nation like ours became a major restraining factor. Despite an asset of having high specificity, RT-PCR for coronavirus disease 2019has its own liability of having low sensitivity. Henceforth, as time passed by, the validity of the rapid diagnostic tests was put into question. In later months, a few centers around our periphery started conducting RT-PCR, but the time taken to obtain the result was long-drawn-out process and the patient who needed urgent neurosurgical intervention at Annapurna Neurological Institute and Allied Sciences had to wait. We would like to share our expedition through peaks and valleys of managing 215 patients during the vicious circle of lockdown and global pandemic.

Ventricular septal rupture after delayed STEMI: A modern management approach.

BACKGROUND: Myocardial infarction associated ventricular septal rupture (VSR) is a potentially catastrophic complication. Though surgical repair remains the definitive treatment, outcomes are poor with high mortality rates.Case and Management: We present the case of a 62-year-old male who presented with a delayed STEMI leading to a VSR and cardiogenic shock. His management strategy included early percutaneous VSR closure and use of an intra-aortic balloon pump and inotropes. This served as a bridge to definitive surgical VSR patch repair while allowing hemodynamic stabilization, end-organ recovery, and myocardial tissue stabilization. CONCLUSION: Mechanical support devices such as intra-aortic balloon pump and Impella combined with percutaneous closure options can serve as a bridge to definitive surgery for VSR. This requires rapid mobilization of a multi-disciplinary structural heart team including advanced imagers, structural interventionalists, and surgeons.

Bilateral thalamic infarction following cerebral venous thrombosis in a patient with ulcerative colitis.

Cerebral Venous Thrombosis is a rare extra-intestinal manifestation of ulcerative colitis. Ulcerative colitis is a hypercoagulable state and, if poorly managed, can predispose to thrombosis, including thrombosis of the cerebral veins.

Cerebral venous sinus thrombosis as a complication of COVID-19 infection - A case report.

INTRODUCTION AND IMPORTANCE: Severe acute respiratory distress syndrome coronavirus 2 is the causative agent of COVID-19 (Coronavirus 2019) infection. Although symptoms are usually associated with the respiratory system, its neurological involvement should not be underestimated. The most common cerebrovascular complication following the infection is ischemic stroke however, CVST (Cerebral Venous Sinus Thrombosis) has been reported. PRESENTATION OF CASE: We report a unique case of a young patient who had a history of headache and abnormal body movement immediately after COVID-19 infection. His brain Computed tomography scan and Magnetic Resonance Imaging (MRI) showed typical images of CVST. He was admitted and treated with Low Molecular weight heparin. DISCUSSION: CVST is a rare form of stroke which may have devastating complications. The diagnosis is clinically challenging due to its non-specific presentation like headache and altered sensorium alone. Inflammatory process and hypoxic state after the virus infection may favor the hypercoagulable state in CVST. Our patient did not have any other predisposing factor for a hypercoagulable state other than the COVID-19 infection.MRI and venography and computed tomographic venography are the preferred modalities. The Patient is generally treated with anticoagulation therapy. CONCLUSION: High index of suspicion of CVST is necessary when a patient presents with unexplained neurological manifestation following a recent COVID-19 infection to prevent from life-threatening complications. Furthermore, clinicians should not underestimate the multisystem involvement of COVID-19.

Cerebral venous thrombosis in a patient with adenomyosis: A case report.

Cerebral venous thrombosis can be caused by different conditions such as infectious, structural, hypercoagulable states, hematological, hormonal, collagen, vascular diseases, and oral contraceptive pills among other causes. Adenomyosis has been rarely associated with Cerebral venous thrombosis (CVT). Increased CA-125 and iron deficiency anemia in adenomyosis may predispose to CVT.

Prevalence of Stroke and Stroke Risk Factors in a South-Western Community of Nepal.

BACKGROUND: Stroke related studies in Nepal are primarily hospital-based and mainly from the capital city. OBJECTIVES: We aimed to estimate the prevalence of stroke and stroke risk factors in the South-Western community of Nepal. METHODS: A cross-sectional study was conducted from May to August 2018 among 549 randomly selected Nepalese participants from diverse ethnicity, aged ≥15 years, in a region with the availability of neurological support facilities. Data were collected using a stroke questionnaire designed for the purpose. Stroke was identified by enumerators using the Balance-Eyes-Face-Arms-Speech-Time (BEFAST) scale, and a senior neurologist confirmed it. We assessed the presence of major risk factors associated with stroke. RESULTS: The crude and age-standardised prevalence of stroke were 2368 and 2967 per 100,000 respectively. Of all the surveyed participants, 61% (n=335) reported consumption of full-fat dairy products >3 days per week, 87.6% (n=481) reported a high intake of salt (>5 g/day), 83.6% (n=459) with a low intake of fruits and vegetables (<400 g/day), 45.2% (n=248) with perceived stress related to work or home, 51.6% (n=283) with financial stress (283, 51.6%), 86.7% (n=457) with low high-density lipoprotein, 96.2% (n=507) with high blood urea nitrogen, 47.1% (n=356) were either overweight or obese 20.4% (n=112) with hypertension and 6.2% (n=34) with diabetes. CONCLUSIONS: The prevalence of stroke in the community of the South-Western part of Nepal is relatively higher than that estimated in South-Asia and global context. Our findings suggest an urgent community intervention, particularly with healthy lifestyles changes for future stroke prevention in the high-risk group.

Clinical significance of 12 lead ECG changes in patients undergoing pericardiocentesis for cardiac tamponade.

INTRODUCTION: The electrocardiogram (ECG) is one of the initial tests done in patients suspected of having a cardiac Tamponade. Historically the emphasis has been on low QRS voltage and electrical alternans, which lacks specificity and sensitivity respectively. Majority of these studies included patients with pericardial effusions without tamponade. Moreover, the influence of different therapeutic interventions such as pericardiocentesis on ECG variables has not been elucidated. OBJECTIVE: To determine the clinical significance of 12 lead ECG changes in patients undergoing pericardiocentesis for cardiac tamponade. METHODS: 144 patients underwent Echo guided pericardiocentesis for cardiac tamponade at a tertiary care hospital over a period of 7 years. We compared 19 EKG variables pre and post procedure. RESULTS: Low voltage was detected in only 31 patients (29%) with 19 (18%) patients having persistent low voltage (p value = 0.0047) after the pericardiocentesis. Electrical alternans was only observed in 25 patients (23%), and persisted in 10 patients (10%) following pericardiocentesis. None of the other EKG variables measured changed reliably post procedure. CONCLUSION: We found that although electrical alternans and low voltage were associated with cardiac tamponade, none of the ECG variables were highly sensitive or specific for the diagnosis, reproducibly changed after drainage or predicted recurrent effusion post-pericardiocentesis.

Aquaporin-4 polymorphisms predict amyloid burden and clinical outcome in the Alzheimer's disease spectrum.

Clearance of amyloid-ß (Aß) from the brain is hypothesized to be mediated by the glymphatic system through aquaporin-4 (AQP4) water channels. Genetic variation of AQP4 may impact water channel function, Aß clearance, and clinical outcomes. We examined whether single-nucleotide polymorphisms (SNPs) of the AQP4 gene were related to Aß neuropathology on [18F]Florbetapir PET in 100 Aß positive late mild cognitive impairment (LMCI) or Alzheimer's disease (AD) patients and were predictive of clinical outcome in prodromal AD patients. AQP4 SNP rs72878794 was associated with decreased Aß uptake, whereas rs151244 was associated with increased Aß uptake, increased risk of conversion from MCI and LMCI to AD, and an increased 4-year rate of cognitive decline in LMCI. AQP4 genetic variation was associated with Aß accumulation, disease stage progression, and cognitive decline. This variation may correspond to changes in glymphatic system functioning and brain Aß clearance and could be a useful biomarker in predicting disease burden for those on the dementia spectrum.

Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment.

Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease for which there is no cure. Mild cognitive impairment (MCI) is considered a prodromal stage of the disease. Molecular imaging with positron emission tomography (PET) allows for the in vivo visualisation and tracking of pathophysiological changes in AD and MCI. PET is a very promising methodology for differential diagnosis and novel targets of PET imaging might also serve as biomarkers for disease-modifying therapeutic interventions. This review provides an overview of the current status and applications of in vivo molecular imaging of AD pathology, specifically amyloid, tau, and microglial activation. PET imaging studies were included and evaluated as potential biomarkers and for monitoring disease progression. Although the majority of radiotracers showed the ability to discriminate AD and MCI patients from healthy controls, they had various limitations that prevent the recommendation of a single technique or tracer as an optimal biomarker. Newer research examining amyloid, tau, and microglial PET imaging in combination suggest an alternative approach in studying the disease process.

No association between variations in extracranial venous anatomy and clinical outcomes in multiple sclerosis patients over 5 years.

BACKGROUND: No longitudinal, long-term, follow-up studies have explored the association between presence and severity of variations in extracranial venous anatomy, and clinical outcomes in patients with multiple sclerosis (MS). OBJECTIVE: This prospective 5-year follow-up study assessed the relationship of variations in extracranial venous anatomy, indicative of chronic cerebrospinal venous insufficiency (CCSVI) on Doppler sonography, according to the International Society for Neurovascular Disease (ISNVD) proposed consensus criteria, with clinical outcomes and disease progression in MS patients. METHODS: 90 MS patients (52 relapsing-remitting, RRMS and 38 secondary-progressive, SPMS) and 38 age- and sex-matched HIs were prospectively followed for 5.5 years. Extracranial and transcranial Doppler-based venous hemodynamic assessment was conducted at baseline and follow-up to determine the extent of variations in extracranial venous anatomy. Change in Expanded Disability Status Scale (∆EDSS), development of disability progression (DP) and annualized relapse rate (ARR) were assessed. RESULTS: No significant differences were observed in MS patients, based on their presence of variations in extracranial venous anatomy at baseline or at the follow-up, in ∆EDSS, development of DP or ARR. While more MS patients had ISNVD CCSVI criteria fulfilled at baseline compared to HIs (58% vs. 37%, p = 0.03), no differences were found at the 5-year follow-up (61% vs. 56%, p = 0.486). DISCUSSION: This is the longest follow-up study assessing the longitudinal relationship between the presence of variations in extracranial venous anatomy and clinical outcomes in MS patients. CONCLUSION: The presence of variations in extracranial venous anatomy does not influence clinical outcomes over the 5-year follow-up in MS patients.

Hypophonia as only presenting symptom in myasthenia gravis - a diagnostic dilemma in poor countries: a case report.

INTRODUCTION: The autoimmune disease myasthenia gravis can mimic a variety of neurological disorders leading to a delay in diagnosis and treatment. In the older population, due to confusion with signs of the ageing process or comorbidities due to ageing, there are many underdiagnosed or misdiagnosed cases of myasthenia gravis. A majority of myasthenia gravis symptoms appear as ocular or motor symptoms and there are very few cases of bulbar symptoms. We present a case of myasthenia gravis with only hypophonia as a clinical feature. CASE PRESENTATION: We present a case of a 51-year-old Madheshi woman whose only complaint was sudden onset of hypophonia which later showed a fluctuating nature throughout the daytime. There was only reduced pitch in her voice with no nasal tone or dysarthria (so-called dysphonia), which created a diagnostic dilemma. Later, a neurological examination and other relevant investigations suggested myasthenia gravis. CONCLUSIONS: Sudden onset and focal neurological deficit can raise the diagnostic dilemma of myasthenia gravis. Relevant laboratory tests and clinical examinations are important to diagnose this disease properly. In resources-deprived nations like Nepal, where several investigations are expensive and access to them is difficult, it becomes very difficult to achieve a solid diagnosis for rare presentations of diseases.

Magnetic resonance imaging in Alzheimer's disease and mild cognitive impairment.

Research utilizing magnetic resonance imaging (MRI) has been crucial to the understanding of the neuropathological mechanisms behind and clinical identification of Alzheimer's disease (AD) and mild cognitive impairment (MCI). MRI modalities show patterns of brain damage that discriminate AD from other brain illnesses and brain abnormalities that are associated with risk of conversion to AD from MCI and other behavioural outcomes. This review discusses the application of various MRI techniques to and their clinical usefulness in AD and MCI. MRI modalities covered include structural MRI, diffusion tensor imaging (DTI), arterial spin labelling (ASL), magnetic resonance spectroscopy (MRS), and functional MRI (fMRI). There is much evidence supporting the validity of MRI as a biomarker for these disorders; however, only traditional structural imaging is currently recommended for routine use in clinical settings. Future research is needed to warrant the inclusion for more advanced MRI methodology in forthcoming revisions to diagnostic criteria for AD and MCI.

REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease.

OBJECTIVE: To investigate whether REM sleep behavior disorder (RBD) is associated with worse motor and cognitive decline in Parkinson disease (PD) METHODS: Four-hundred twenty-one drug-naive patients with early-stage PD and 196 controls without PD were included in this study. All participants underwent a [123I]FP-CIT SPECT scan, CSF assessment, 3-tesla MRI, and thorough clinical assessments. RESULTS: At cross-sectional analyses, patients with PD and probable RBD (PD-RBD) had lower CSF ß-amyloid 1-42 (Aß42) levels and higher total tau to Aß42 CSF ratio, higher nonmotor symptoms burden, and worse scores on neuropsychological tests of processing speed, visuospatial functioning, and delayed recognition memory compared to patients with PD without RBD. At longitudinal analyses, the presence of RBD was associated with faster motor progression (hazard ratio [HR] = 1.368, 95% confidence Interval [CI] = 1.036-1.806; p = 0.027) and cognitive decline (HR = 1.794, 95% CI = 1.163-2.768; p = 0.008) over 60-month follow-up. The presence of RBD was a predictor for motor progression only in patients with PD who had both low α-synuclein levels and low [123I]FP-CIT uptake in the striatum (HR = 2.091, 95% CI = 1.116-3.918; p = 0.021) and a predictor for cognitive decline only in patients with PD who had both low Aß42 and low α-synuclein levels (HR = 2.810, 95% CI = 1.462-5.400; p = 0.002). In the population of controls without PD, the presence of RBD was not associated with cognitive decline or any baseline pathologic changes. CONCLUSION: The presence of RBD in PD is associated with faster motor progression in patients with greater synuclein and dopaminergic pathology, and with higher risk of cognitive decline in patients with greater synuclein and amyloid pathology. Our findings provide an important direction toward understanding phenotypes and their prognosis in PD.

Association of parental methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in couples with unexplained recurrent pregnancy loss.

OBJECTIVE: The aim of this study was to identify the association of parental MTHFR C677T gene polymorphism in couples with and without RPL history. RESULTS: During the study, 21.4% (15/70) of Ala222Val polymorphism was observed among RPL couples while no polymorphism was seen among normal, healthy couples. Our study did not find any association between MTHFR C677T polymorphism and gender (p > 0.05), gestational period (p > 0.05), geographical region (p > 0.05) and menstrual history (p > 0.05). However, significant association was seen between MTHFR C677T polymorphism and number of losses (p < 0.05), concluding that the risk of the polymorphism increased with the increase in number of losses. Significant variation in the MTHFR C677T genotype with number of losses among RPL couples were seen but not with other study variables.

Leptomeningeal contrast enhancement is associated with progression of cortical atrophy in MS: A retrospective, pilot, observational longitudinal study.

BACKGROUND: Leptomeningeal contrast enhancement (LM CE) has been recently described in multiple sclerosis (MS) patients as a potential in vivo marker of cortical pathology. OBJECTIVES: To investigate the association of LM CE and development of cortical atrophy in 50 MS patients (27 relapsing-remitting (RR) and 23 secondary-progressive (SP)) followed for 5 years. METHODS: The presence and number of LM CE foci were assessed only at the 5-year follow-up using three-dimensional (3D) fluid-attenuated inversion recovery magnetic resonance imaging (MRI) sequence obtained 10 minutes after single dose of gadolinium injection on 3T scanner. The percentage change in whole brain, cortical and deep gray matter (GM) volumes, and lesion volume (LV) was measured between baseline and the 5-year follow-up. RESULTS: In total, 25 (50%) of MS patients had LM CE at the 5-year follow-up. Significantly more SPMS patients (12, 85.7%) had multiple LM CE foci, compared to those with RRMS (2, 18.2%) ( p = 0.001). MS patients with LM CE showed significantly greater percentage decrease in total GM (-3.6% vs -2%, d = 0.80, p = 0.006) and cortical (-3.4% vs -1.8%, d = 0.84, p = 0.007) volumes and greater percentage increase in ventricular cerebrospinal fluid (vCSF) volume (22.8% vs 9.9%, d = 0.90, p = 0.003) over the follow-up, compared to those without. CONCLUSION: In this retrospective, pilot, observational longitudinal study, the presence of LM CE was associated with progression of cortical atrophy over 5 years.