Aging and multiple sclerosis.

The life expectancy and average age of persons with multiple sclerosis (MS) have increased significantly during the last two decades. The introduction of disease-modifying therapies and a better delineation and understanding of the superimposed comorbidities often diagnosed in MS patients are probably the most important factors accountable for the increase in aging MS population worldwide. Healthcare teams must therefore address the problems arising due to advancing age superimposed on this chronic neurologic disease. In this review, we focus on the physiology of aging, its effects on MS disease course, and the pathological and immunological changes associated with aging and disease progression. Additionally, we discuss the common comorbidities that occur in aging persons with MS that may arise either as a result of the aging process or from relentless chronic MS disease progression as well as the challenges on differentiating the two processes for a more appropriate therapeutic approach.

Factors associated with benign multiple sclerosis in the New York State MS Consortium (NYSMSC).

BACKGROUND: This retrospective analysis explored prognostic factors associated with a benign multiple sclerosis (BMS) disease course at baseline and over the 4-year follow-up. METHODS: Patients from the centralized New York State Multiple Sclerosis Consortium registry were classified as having BMS according to 3 different criteria centered on disease duration and disability. Additional analyses explored prognostic factors associated with BMS using the most conservative disability criteria (Expanded Disability Status Scale ≤2 and disease duration ≥10 years). RESULTS: Among 6258 patients who fulfilled eligibility criteria, 19.8 % to 33.3 % were characterized as having BMS, at baseline depending on classification criteria used. Positive prognostic factors for BMS at baseline included female sex (p < 0.0001) and younger age at onset (p < 0.0001); negative prognostic factors included progressive-onset type of MS and African-American race. Of the 1237 BMS patients (per most conservative criteria), 742 were followed for a median of 4 years to explore effect of disease-modifying treatment (DMT) on benign status. DMT (p = 0.009) and longer disease duration (p = 0.007) were the only significant positive predictors of maintaining BMS at follow-up. The protective effect was stronger for patients taking DMT at both enrollment and follow-up (OR = 0.71; p = 0.006). CONCLUSIONS: There is a need for development of more reliable prognostic indicators of BMS. Use of DMT was significantly associated with maintaining a benign disease state.

Higher weight in adolescence and young adulthood is associated with an earlier age at multiple sclerosis onset.

BACKGROUND: Growing evidence suggests an association between adolescent obesity and increased risk of multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to investigate whether weight or body mass index (BMI) in adolescence and young adulthood was associated with age at MS symptom onset. METHODS: Our cohort is comprised of a sub-group of 184 women enrolled in the New York State MS Consortium registry. Individuals were asked to recall their weight at the time of first menstruation and at age 25. BMI was calculated accordingly for age 25. Regression analyses were carried out to investigate the association between weight or BMI and age at onset. RESULTS: Weight at menarche was significantly related to younger age at symptom onset (ß = -0.073, p = 0.001). These results were also found at age 25 for weight (ß = -0.080, p < 0.001) and BMI (ß = -0.448, p = 0.001). Significantly earlier disease onset (26.9 years ±9.9) was observed in individuals who were overweight at 25 compared to those who were not overweight (32.1 years ±9.2, p = 0.006). CONCLUSIONS: Women who reported higher weight in adolescence and BMI in early adulthood were younger at MS onset. Future research should investigate whether there is a causal link between body weight and MS, as prevention lifestyle and dietary interventions could be implemented.

Characteristics influencing therapy switch behavior after suboptimal response to first-line treatment in patients with multiple sclerosis.

BACKGROUND: Factors driving disease-modifying therapy (DMT) switch behavior are not well understood. OBJECTIVE: The objective of this paper is to identify patient characteristics and clinical events predictive of therapy switching in patients with suboptimal response to DMT. METHODS: This retrospective study analyzed patients with relapsing-remitting multiple sclerosis (MS) and a suboptimal response to initial therapy with either interferon ß or glatiramer acetate. Suboptimal responders were defined as patients with ≥1 MS event (clinical relapse, worsening disability, or MRI worsening) while on DMT. Switchers were defined as those who changed DMT within six to 12 months after the MS event. RESULTS: Of 606 suboptimal responders, 214 (35.3%) switched therapy. Switchers were younger at symptom onset (p = 0.012), MS diagnosis (p = 0.004), DMT initiation (p < 0.001), and first MS event (p = 0.011) compared with nonswitchers. Compared with one relapse alone, MRI worsening alone most strongly predicted switch behavior (odds ratio 6.3; 95% CI, 3.1-12.9; p < 0.001), followed by ≥2 relapses (2.8; 95% CI, 1.1-7.3; p = 0.040), EDSS plus MRI worsening (2.5; 95% CI, 1.1-5.9; p = 0.031) and EDSS worsening alone (2.2; 95% CI, 1.2-4.1; p = 0.009). CONCLUSIONS: Younger patients with disease activity, especially MRI changes, are more likely to have their therapy switched sooner than patients who are older at the time of MS diagnosis and DMT initiation.

MRI characteristics of familial and sporadic multiple sclerosis patients.

PURPOSE: To investigate the MRI characteristics in a large cohort of multiple sclerosis (MS) patients with and without a family history of MS. METHODS: Enrolled in this prospective study were 758 consecutive MS patients (mean age 46.2 ± 10.1 years, disease duration 13.6 ± 9.2 years and EDSS 3.4 ± 2.1), of whom 477 had relapsing-remitting, 222 secondary-progressive, and 30 primary-progressive disease courses and 29 had clinically isolated syndrome. One hundred and ninety-six patients (25.9%) had a positive family history of MS. Patients were assessed using measurements of lesions, brain atrophy, magnetization transfer ratio (MTR) and diffusion-weighted imaging. RESULTS: The familial MS group had greater T1-lesion volume (p=0.009) and a trend for lower MTR of T1-lesion volume (p=0.047) than the sporadic MS group. No clinical differences were found between familial versus sporadic group, or by a degree of affected relative subgroups. CONCLUSIONS: While familial MS was associated with more severe T1-lesion volume and its MTR characteristics, there were no clinical status differences between familial and sporadic MS patients. Therefore, a better understanding of the genetic and/or epigenetic influences causing these differences can advance the understanding and management of MS.

Cognitive impairment is associated with reduced bone mass in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) has been associated with reduced bone mineral density (BMD), yet the underlying causes are not fully known. The recent discovery that bone homeostasis is directly regulated by the brain led us to hypothesize that it may be impaired by MS pathology. As cognitive impairment (CI) is a well-documented correlate of MS-related brain pathology, we tested the hypothesis that it is associated with reduced BMD. OBJECTIVE: We aimed to determine if CI is associated with reduced BMD in patients with MS. METHODS: We retrospectively studied the medical records of 56 patients with MS, ≤50 years old, with Expanded Disability Status Scale score ≤4.5 and with dual X-ray absorptiometry (DEXA) BMD measurement within 1 year of neuropsychological testing with a standard battery (MACFIMS). RESULTS: In total, 23 (41.1%) MS patients had osteopenia or osteoporosis. Mean femur BMD was significantly lower in patients with MS with CI (0.89±0.12 g/cm(2)) compared with intact patients (0.99±0.17 g/cm(2), p=0.009). In the cognitively impaired group, 59.3% had either osteopenia or osteoporosis, compared with 24.1% in the non-cognitively impaired group (odds ratio=4.57, p=0.008). CONCLUSION: CI is associated with reduced BMD in patients with MS, suggesting that central mechanisms involved in bone homeostasis may be directly impaired by MS-related inflammatory and neurodegenerative processes.

Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis.

BACKGROUND: The breakdown of the blood-brain-barrier vascular endothelium is critical for entry of immune cells into the MS brain. Vascular co-morbidities are associated with increased risk of progression. Dyslipidemia, elevated LDL and reduced HDL may increase progression by activating inflammatory processes at the vascular endothelium. OBJECTIVE: To assess the associations of serum lipid profile variables (triglycerides, high and low density lipoproteins (HDL, LDL) and total cholesterol) with disability and MRI measures in multiple sclerosis (MS). METHODS: This study included 492 MS patients (age: 47.1 ± 10.8 years; disease duration: 12.8 ± 10.1 years) with baseline and follow-up Expanded Disability Status Score (EDSS) assessments after a mean period of 2.2 ± 1.0 years. The associations of baseline lipid profile variables with disability changes were assessed. Quantitative MRI findings at baseline were available for 210 patients. RESULTS: EDSS worsening was associated with higher baseline LDL (p = 0.006) and total cholesterol (p = 0.001, 0.008) levels, with trends for higher triglyceride (p = 0.025); HDL was not associated. A similar pattern was found for MSSS worsening. Higher HDL levels (p < 0.001) were associated with lower contrast-enhancing lesion volume. Higher total cholesterol was associated with a trend for lower brain parenchymal fraction (p = 0.033). CONCLUSIONS: Serum lipid profile has modest effects on disease progression in MS. Worsening disability is associated with higher levels of LDL, total cholesterol and triglycerides. Higher HDL is associated with lower levels of acute inflammatory activity.

Equol status modifies the association of soy intake and mammographic density in a sample of postmenopausal women.

Only 30% to 50% of people produce the daidzein-metabolite equol after eating soy. We conducted a cross-sectional study of the associations between equol status, intake of soy foods, and mammographic density in a sample of postmenopausal women recruited at a radiology clinic near Buffalo, New York. Participants were 48 to 82 years old, had no history of cancer or breast reduction/augmentation, and no recent use of antibiotics or hormones. Percent density was measured by computer-assisted analysis of digitized images of craniocaudal films. Equol status was assessed using a soy-challenge protocol and usual soy intake by questionnaire. General linear models were used to assess independent and joint effects of equol status and intake of soy on multivariate adjusted percent density (covariates included age, body mass index, parity, age at first birth, and ever use of combined hormone therapy). Of 325 enrolled, 232 (71%) participants completed study assessments and are included in the present analysis. Mean percent density was 34% (+/-18%). Seventy-five (30%) participants were producers of equol. Forty-three (19%) participants reported regularly eating >1 soy food or supplement/wk. There were no significant independent associations of equol status or soy intake with percent density, but the interaction between these factors was significant (P < 0.01). Among equol producers, those with weekly soy intake had lower percent density (30.7% in weekly consumers of soy versus 38.9% in others; P = 0.08); among nonproducers, weekly soy intake was associated with higher percent density (37.5% in weekly soy consumers versus 30.7% in others; P = 0.03). Results suggest that equol producers and nonproducers may experience different effects of dietary soy on breast tissue.

Fatigue and Mood States in Nursing Home and Nonambulatory Home-Based Patients with Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic, progressively disabling condition of the central nervous system. We sought to evaluate and compare mood states in patients with MS with increased disability residing in nursing homes and those receiving home-based care. METHODS: We conducted a cross-sectional analysis of the New York State Multiple Sclerosis Consortium to identify patients with MS using a Kurtzke Expanded Disability Status Scale (EDSS) score of 7.0 or greater. The nursing home group was compared with home-based care patients regarding self-reported levels of loneliness, pessimism, tension, panic, irritation, morbid thoughts, feelings of guilt, and fatigue using independent-samples t tests and χ2 tests. Multivariate logistic regression analyses were used to investigate risk-adjusted differences in mood states. RESULTS: Ninety-four of 924 patients with EDSS scores of at least 7.0 lived in a nursing home (10.2%). Nursing home patients were less likely to use disease-modifying therapy and had higher mean EDSS scores compared with home-based patients. However, nursing home patients were less likely than home-based patients to report fatigue (odds ratio [OR] for no fatigue, 3.8; 95% CI, 2.1-7.2), feeling tense (OR for no tension, 1.7; 95% CI, 1.1-2.7), and having feelings of pessimism (OR for no pessimism, 1.8; 95% CI, 1.2-2.8). CONCLUSIONS: The nursing home patients with MS were less likely to report fatigue, pessimism, and tension than those receiving home-based care. Further studies should examine ways of facilitating a greater degree of autonomy and decision-making control in MS patients receiving home-based care.

Time interval providing highest yield for initial EEG in patients with new onset seizures.

PURPOSE: Timing providing highest yield of initial electroencephalogram (EEG) after new onset unprovoked seizures, is an important and practical issue both in diagnosis and patient care. Current guidelines suggest routine EEG is the standard of care in work-up. However, yield of the initial EEG and exact timeframe in which to perform remain unclear and standardization in both adult and pediatric populations is still lacking. Our objective was to determine a concrete timeframe to perform initial EEG in patients with new onset unprovoked seizures and provide greater yield of EEG benefits in patient management. METHOD: This is a retrospective chart review study of both pediatric and adult patients identified from EEG Database over 1999-2014 located at Kaleida Health at Buffalo using keyword "new onset seizure". RESULTS: The percentage of EEGs revealing epileptiform discharges is much higher if EEGs are performed within 12hours after the seizure onset compared to studies done beyond this timeframe (53.1% versus 23.9%). There was no significant difference in the presence of epileptiform discharges if the study is done 12hours after the seizure onset. Odds ratio was 3.599 (the presence of epileptiform discharges) with a Confidence Interval of 1.691-7.660 (p=0.001) within first 12hours of initial event. CONCLUSION: This study demonstrated statistical significance in yield of epileptiform discharges by performing EEG within the first 12hours of seizure onset, in both adult and pediatric populations, which should be considered for clinical practice and patient care.

Low-Dose Medication and Long-Term Outcome in Myasthenia Gravis.

OBJECTIVES: Many advances have been made in the diagnosis, treatment, and management of myasthenia gravis (MG) and most patients will eventually progress to experience minimal manifestations (MM) of the disease or remission. However, there is a paucity of literature on medication dosing needed to achieve such a favorable clinical status in the long term. The objective of this article was to (1) study the course of MG and identify clinical predictors of maintenance of eventual disease remission or minimal manifestations and (2) determine if patients on low-dose medications have comparable MG Foundation of America (MGFA) scores and postintervention statuses (PIS) with those on conventional therapeutic dosing. METHODS: This is a retrospective longitudinal chart review of 74 patients with MG. A subset of 28 of 74 patients diagnosed with MG after 2000 who were followed for at least 3 consecutive years from the year of diagnosis were also analyzed. An annual MGFA score, PIS, medication doses, and thymectomy status were obtained. Remission or MM of disease was defined as MGFA clinical classification <2 that persisted over the past 2 follow-up visits. RESULTS: Thirty-four of 74 patients were on low-dose medications at last follow-up. There was no statistical difference between medication dosages and MGFA scores. In a subset of 28 patients, 23 (88.5%) with eventual disease remission or MM at last follow-up had an MGFA class <2 at their third year of diagnosis. In contrast, only 3 of 9 subjects with more symptomatic disease had similar results (P = 0.005). In terms of PIS at last follow-up, most patients were either in complete stable remission, pharmacologic remission, or MM status. Most patients (78.3%) had an MGFA class of 0 or 1 at last follow-up; 45% were on low-dose medications. CONCLUSIONS: Most patients with MG will realize disease stability characterized by either remission or MM status. A significant number of such patients were able to be maintained on low doses of medications to treat MG. The MGFA class at year 3 of diagnosis is a clinical predictor of long-term disease prognosis. There was no statistical difference between medication doses and MGFA scores at last follow-up.

Decreased risk of cancer in multiple sclerosis patients and analysis of the effect of disease modifying therapies on cancer risk.

BACKGROUND: Although dysimmunity is considered an important link between multiple sclerosis (MS), family history and cancer risk, their relationship to the use of disease modifying therapies (DMT) is not fully understood. OBJECTIVE: To assess the observed versus expected number of cancers in MS patients, and family history of cancer, among DMT users and DMT naïve patients. METHODS: Cancer, DMT use, and family history of cancer were assessed using the New York State Multiple Sclerosis Consortium (NYSMSC) registry. Self-reported cancers in MS patients were tested for associations with DMT use, family history of cancer and other factors. Expected number of cancer cases was estimated using age- and gender-specific prevalence and incidence rates from the general population. RESULTS: The prevalence of cancer in males and females in the NYSMSC cohort was lower than expected (p<0.001). Patients with cancer were older at MS diagnosis and more likely to be female (p<0.001). MS patients with a personal history of cancer were more likely to report DMT use (p<0.001) and family history of cancer (p<0.001). Multivariable analysis did not support a higher risk of cancer after DMT initiation. CONCLUSIONS: We report a lower than expected number of cancer cases in MS patients compared to the general population. MS patients with a personal history of cancer were more likely to report DMT use suggesting that DMTs may abrogate the lower incidence of cancer in MS.

Disease modifying therapies use associated with comorbid autoimmune diseases in multiple sclerosis patients.

BACKGROUND: The relation between the use of disease modifying therapies (DMT׳s) and the occurrence of comorbid autoimmune diseases (AID׳s) in multiple sclerosis (MS) patients is still unclear. OBJECTIVE: To investigate the difference in duration from MS symptom onset to first reported AID in subjects using DMT׳s vs. DMT naïve. Type and prevalence of comorbid AID׳s was also investigated. METHODS: Data was extracted from the New York State MS Consortium (NYSMSC) registry and comprised of MS patients with a minimum of 5 years follow-up. After exclusion, 1792 patients were enrolled in the study, 1478 had no AID, and 314 patients had comorbid AID׳s that developed after the initial enrollment. Patients who had an AID were divided into two groups: those with an AID after DMT initiation (n=281) and patients with an AID who were DMT naïve (n=33). Logistic regression analysis was used to test differences in duration between MS symptom onset and the development of AID between the two groups while adjusting for confounders RESULTS: DMT use did not change the frequency of self-reported AID (17.2 vs. 20.4%). However, the duration between first MS symptom onset and the initial reported occurrence of a comorbid AID was significantly shorter in the DMT user group (192 months±115) compared to the DMT naïve group (262 months±107, p=.002). CONCLUSION: There were no group differences between DMT users vs. DMT naïve subjects with regards to AID frequency. The DMT user group reported the development of an AID earlier than the DMT naïve group. Further studies that can identify patients with higher risk for developing AID׳s is warranted.

Characteristics of refractory vs. medically controlled epilepsy patients with obstructive sleep apnea and their response to CPAP treatment.

UNLABELLED: Obstructive sleep apnea (OSA) commonly coexists with epilepsy, and treatment of OSA may decrease seizure frequency. However, it is unclear whether patients with medically refractory epilepsy have a higher incidence of OSA compared with well-controlled epilepsy patients and whether the two groups carry different risk factors. PURPOSE: This study aimed to investigate the presence of OSA in patients with refractory vs. well-controlled epilepsy and their associated risk factors. We also assessed the benefits of treatment of OSA with continuous positive airway pressure (CPAP) in refractory epilepsy patients. METHODS: We retrospectively reviewed data from patients who presented to the Jacobs Neurological Institute Comprehensive Epilepsy Center of University at Buffalo from 2007 to 2010. RESULTS: There is a tendency for much higher incidence of OSA in our epilepsy population compared with the general population (15.2% vs. 4.41%). For patients with well-controlled epilepsy, older age, male gender, and higher seizure frequency were predictors of a diagnosis of OSA. However, in medically refractory epilepsy patients, diabetes and snoring predicted a diagnosis of OSA. Treatment of OSA with CPAP in refractory epilepsy patients improved their seizure control (p<0.02). CONCLUSION: This study confirms that OSA is common in epilepsy patients and treatment of OSA can improve seizure control in medically refractory cases. Patients with refractory epilepsy who have diabetes are more likely to have OSA.

The nervous system's potential role in multiple sclerosis associated bone loss.

Osteoporosis is a degenerative bone disease that causes significant morbidity and mortality in multiple sclerosis (MS) patients; the pathogenesis of this disease being poorly understood in the context of MS. Osteoporosis is seen more frequently in MS patients than in healthy controls matched for age and sex. Extensively studied factors, including impaired ambulation and the use of steroids, do not appear to completely account for the phenomenon. This review summarizes common risk factors, physiologic and genetic, that may contribute to the etiology and progression of osteoporosis in MS patients as well as providing insight into nervous system control of bone metabolism and homeostasis.

Estrogen metabolism and mammographic density in postmenopausal women: a cross-sectional study.

BACKGROUND: Prospective studies have consistently found that postmenopausal breast cancer risk increases with circulating estrogens; however, findings from studies of estrogens and mammographic density (MD), an intermediate marker of breast cancer risk, have been inconsistent. We investigated the cross-sectional associations of urinary estrogens, and their 2-, 4-, and 16-hydroxylated metabolites with MD. METHODS: Postmenopausal women without breast cancer (n = 194), ages 48 to 82 years, and reporting no current menopausal hormone therapy use were enrolled at a clinic in Western NY in 2005. Urinary estrogens and estrogen metabolites were measured using mass spectrometry. Percent MD and dense area (cm(2)) were measured using computer-assisted analyses of digitized films. Linear regression models were used to estimate associations of log-transformed estrogen measures with MD while adjusting for age, body mass index (BMI), parity, and past hormone therapy use. RESULTS: Urinary concentrations of most individual estrogens and metabolites were not associated with MD; however, across the interdecile range of the ratio of parent estrogens (estrone and estradiol) to their metabolites, MD increased by 6.8 percentage points (P = 0.02) and dense area increased by 10.3 cm(2) (P = 0.03). Across the interdecile ranges of the ratios of 2-, 4-, and 16-hydroxylation pathways to the parent estrogens, MD declined by 6.2 (P = 0.03), 6.4 (P = 0.04), and 5.7 (P = 0.05) percentage points, respectively. All associations remained apparent in models without adjustment for BMI. CONCLUSION: In this study of postmenopausal women, less extensive hydroxylation of parent estrogens was associated with higher MD. IMPACT: Hydroxylation of estrogens may modulate postmenopausal breast cancer risk through a pathway involving MD.

Indicators of sexual and somatic development and adolescent body size in relation to prostate cancer risk: results from a case-control study.

OBJECTIVES: To examine the relationship between the indicators of sexual and somatic development (ie, age at first shaving and maximal shoe size) and adolescent anthropometric characteristics (ie, body size at age 10 to 13 years) and prostate cancer risk. METHODS: We analyzed the data from a population-based case-control study in Erie and Niagara Counties, New York. The participants were 64 men with incident, primary, histologically confirmed, clinically apparent (Stage B and greater) prostate cancer and 218 controls, who had been frequency matched by age and residential area. Information regarding the variables of interest was self-reported. We compared the adjusted mean age at first shaving and age at maximal shoe size and calculated the odds of body size at ages 10 to 13 years using logistic regression models. RESULTS: The patients showed no evidence of older age at first shaving (adjusted mean, 18.0 versus 17.8 years, P = 0.46) or significant evidence of older age at the maximal shoe size (20.1 versus 17.6 years, P <0.05). The participants who defined themselves as being as heavy as or heavier than their peers at age 10 to 13 years showed a decreased prostate cancer risk compared with participants who were thinner than their peers (odds ratio 0.36, 95% confidence interval 0.15 to 0.83; and odds ratio 0.38, 95% confidence interval 0.17 to 0.87, respectively). CONCLUSIONS: Our results support a role for the indicators of somatic development and adolescent body size in predicting prostate cancer risk, suggesting that risk determinants operating early in life affect men's subsequent prostate cancer risk.

Risk of ovarian cancer associated with BMI varies by menopausal status.

Obesity has been linked to increased risk of several malignancies, but the role of obesity in the etiology of ovarian cancer remains unclear. Therefore, a hospital-based case-control study was conducted to investigate the association between body size and risk of ovarian cancer. Participants included 427 women with primary, incident ovarian cancer and 854 cancer-free controls. All participants received medical services at Roswell Park Cancer Institute in Buffalo, NY between 1982 and 1998 and completed a comprehensive epidemiological questionnaire. The instrument included questions regarding height and usual wt prior to survey. Participants were classified as underweight/normal (BMI < or = 24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), or obese (BMI > or = 30.0 kg/m2). Compared with underweight/normal participants, being overweight (adjusted odds ratio [OR] = 1.02; 95% CI 0.77-1.36) or obese (adjusted OR = 1.17; 95% CI 0.84-1.65) was not significantly associated with an elevated risk of ovarian cancer. After stratification by menopausal status, BMI showed no significant association to ovarian cancer risk among postmenopausal women (> or = 50 y old). However, among premenopausal women (<50 y old), those classified as obese had a significantly increased risk (adjusted OR = 2.19; 95% CI 1.19-4.04) compared with women classified as normal/underweight. These findings suggest a potential influence of menopausal status on the total endogenous hormonal environment, including estrogens, androgens, and insulin-like growth factors, when considering the association between body size and ovarian cancer risk. In light of the fact that obesity is a modifiable risk factor, further investigation on this topic is warranted.