Learning whom not to trust across early and middle adolescence: A longitudinal neuroimaging study to trusting behavior involving an uncooperative other.

Longitudinal changes in trusting behavior across adolescence and their neural correlates were examined. Neural regions of interest (ROIs) included the medial prefrontal cortex (mPFC), dorsal anterior cingulate cortex (dACC), left anterior insula (AI), bilateral ventral striatum (VS), and right dorsal striatum (DS). Participants (wave 1 age: M = 12.90) played the investor in a Trust Game with an uncooperative trustee three times (1-year interval). Analyses included 77 primarily Dutch participants (33 females). Participants decreased their investments with wave. Furthermore, activity was heightened in mPFC, dACC, and DS during investment and repayment, and in right VS (investment) and AI (repayment). Finally, DS activity during repayment increased with wave. These findings highlight early-middle adolescence as an important period for developing sensitivity to uncooperative behavior.

The development of adolescent trust behavior.

Interpersonal trust shows developmental changes during adolescence. The current study used a longitudinal design to examine the development of trust behavior, the presence of gender differences in these developmental trajectories, and the association between individual differences in these developmental trajectories and perspective-taking abilities. The participants played a trust game with a hypothetical trustworthy partner and a trust game with a hypothetical untrustworthy partner in 3 consecutive years (Mage = 12.55 years, Mage = 13.54 years, and Mage = 14.54 years). Concerning the development of trust behavior, the results showed an age-related increase in initial trust behavior and indicated increasingly adaptive trust behavior with age during untrustworthy interactions, whereas no evidence was found for age-related changes in the adaptation of trust during trustworthy interactions. Gender differences were found for the development of initial trust behavior (with boys showing a stronger increase with age than girls), whereas no support was found for the presence of gender differences in the developmental trajectories of adaptive trust behavior during trustworthy and untrustworthy interactions. Furthermore, no evidence was found for perspective-taking abilities to explain individual differences in the development of initial trust behavior or in the development of adaptive trust behavior during trustworthy and untrustworthy interactions. The results provide evidence that, during adolescence initial trust behavior increased with age, more for boys than for girls, and that both boys and girls showed a stronger adaptive response to the untrustworthy partner but not to the trustworthy partner.

A case of GNE myopathy mimicking hereditary motor neuropathy.

A 36-year-old woman who presented with upper limb distal weakness since the age of 15 years, with gradual progression to the lower limbs, is reported. Hereditary motor neuropathy was initially suspected based on distal weakness and hyporeflexia; however, whole exome sequencing accidentally revealed a compound heterozygous variant in the GNE gene, and ultrasound revealed increased homogeneous echogenicity in the involved muscles, which is characteristic of myopathic changes. Muscle magnetic resonance imaging revealed fatty infiltration in all limb muscles, sparing the triceps brachii, vastus lateralis and vastus medialis. Muscle biopsy revealed intracytoplasmic rimmed vacuole, supporting the diagnosis of GNE myopathy.

Long-term efficacy of miglustat in paediatric patients with Niemann-Pick disease type C.

Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease characterized by progressive neurological manifestations. Oral miglustat was first approved for the treatment of children and adults with NP-C in Europe in 2009. There are still relatively few published data on the long-term efficacy and safety of miglustat in patients with NP-C in clinical practice. We report the effects of up to 6 years of treatment with miglustat 100 mg t.i.d. in five children. Overall, 3/5 patients displayed progressive dysphagia before starting miglustat, and 4/5 showed marked cognitive and/or motor impairment. The mean age at treatment start was 11.6 years, and the median (range) duration of therapy so far is 4 (4.1 to 6.1) years. No treatment dose alterations were required, but therapy was interrupted for 1-3 months at least once in all patients due to supply issues. Swallowing function was stabilised during miglustat therapy, with no significant increase in Han dysphagia scale or aspiration-penetration index scores among four evaluable patients (p > 0.05). Scores on the mini-mental state examination indicated an improvement in cognitive function during the first 3-6 months of miglustat therapy, followed by stabilisation up to 5 years. Ambulatory function remained stable for at least the first 2 years of treatment in most patients, but there was a trend towards deterioration thereafter, possibly related to treatment interruptions. The safety/tolerability profile of miglustat was similar to previous clinical studies, although reports of gastrointestinal disturbances were rare. Overall, miglustat appeared to stabilise key parameters of neurological disease progression.

The effect of incorrect prior information on trust behavior in adolescents.

During adolescence, social cognition and the brain undergo major developments. Social interactions become more important, and adolescents must learn that not everyone can be trusted equally. Prior knowledge about the trustworthiness of an interaction partner may affect adolescents' expectations about the partner. However, the expectations based on prior knowledge can turn out to be incorrect, causing the need to respond adaptively during the interaction. In the current fMRI study, we investigated the effect of incorrect prior knowledge on adolescent trust behavior and on the neural processes of trust. Thirty-three adolescents (Mage = 17.2 years, SDage = 0.5 years) played two trust games with partners whose behavior was preprogrammed using an algorithm that modeled trustworthy behavior. Prior to the start of both games, participants received information suggesting that the partner in one game was untrustworthy (raising incorrect expectations) and the partner in the other game trustworthy (raising correct expectations). Results indicated that participants adapted their trust behavior following incorrect prior expectations. No evidence for a change in trust behavior was shown when prior expectations were correct. fMRI analyses revealed that when receiving the partner's response, activity in the dorsolateral prefrontal cortex and in the superior parietal gyrus were increased when participants had incorrect expectations about the partner compared to when participants had correct expectations. When making trust decisions, no significant differences in neural activity were found when comparing the two games. This study provides insight into how adolescent trust behavior and neural mechanisms are affected by expectations and provides an increased understanding of the factors that influence adolescent social interactions.

Quantitative examination of early diabetes by light-emitting diodes light-induced pupillary light reflex.

This study investigated the abnormal pupillary light reflex in patients with early diabetes mellitus (DM) without retinopathy by using a custom-made noninvasive portable pupilometer. The pupilometer recorded and analyzed the pupillary light reflex. Two light intensities, 0.2 cd and 1.2 cd, and four wavelengths of stimulus light-white (400 nm-800 nm), red (640 ± 5 nm), green (534 ± 5 nm), and blue (470 ± 5 nm)-were used to stimulate the pupil for 10 ms. The pupillary response was recorded for 15 s. A total of 40 healthy people and 40 people with DM without retinopathy participated in the experiment at the National Taiwan University Hospital. The mean and standard deviation of DM duration were 4.5 years and 3.9 years. Of the 16 indices, the duration that pupil restores from its minimum size to half of its resting size (DRP), maximum pupil restoration velocity (MRV), and average restoration velocity (ARV) exhibited the most significant differences between the healthy people and those with DM. Compared with healthy participants, DRP was 16.33% higher, and MRV and ARV were 17.45% and 4.58% lower, respectively, in those with DM. This might be attributable to the sympathetic nervous system (SNS) controlling the dilator muscle during the dark-adapted period and relaxing the pupil; the SNS had few degenerated nerve endings in people with DM. The three aforementioned indices might be used to evaluate the severity of autonomic neuropathy in early DM.

Stabilization of blood methylmalonic acid level in methylmalonic acidemia after liver transplantation.

Methylmalonic acidemia with complete mutase deficiency (mut(0) type) is an inborn error of metabolism with high mortality and morbidity. LT has been suggested to be a solution to this disease, but elevation of urinary and blood MMA was still observed after LT. In this study, we measured dry blood spot MMA and its precursor propionyl-carnitine (C3-carnitine) for mut(0) patients. The results revealed that when C3-carnitine rose during metabolic stress, MMA rose exponentially (up to 1000 micromol/L) in patients who did not undergo LT. In patients who underwent LT, MMA rose to 100-200 micromol/L when C3-carnitine reached 10-20 micromol/L. However, when C3-carnitine rose further to 40-50 micromol/L, MMA levels just stayed put. Therefore, LT stabilized blood MMA level, though there might be a threshold for blood MMA clearance by the donor liver. This finding should be critical to understand the long-term outcome for LT in methylmalonic acidemia.

Treatment of Niemann-Pick disease type C in two children with miglustat: initial responses and maintenance of effects over 1 year.

Niemann-Pick disease type C (NP-C) is a lipid storage disorder characterized by the accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system of certain cells in the central nervous system (CNS) and visceral organs. Clinical symptoms include progressive neurological deterioration and visceral organomegaly. Miglustat, a small iminosugar molecule approved for the treatment of Gaucher disease, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step in glycosphingolipid synthesis. The physicochemical properties of miglustat allow it to cross the blood-brain barrier and suggest possible benefits in lysosomal storage diseases affecting the CNS. Here, we present findings in two children with NP-C, aged 14 years (patient 1) and 9 years (patient 2), treated with miglustat for 1 year. Before treatment, patient 1 presented with severe difficulties in swallowing and walking, and patient 2 with problems mostly affecting communication and social interaction. Videofluoroscopic studies in patient 1 demonstrated a substantial improvement in swallowing by month 6 of treatment, and ambulation index measurements indicated improved walking. Mini Mental-State Examination (MMSE) assessments in patient 2 showed cognitive improvement by month 6, which was sustained up to month 12. Liver/spleen volume and plasma chitotriosidase activities were stabilized in both cases. There was no weight loss during treatment. Patient 1 experienced severe but self-limiting paresthesia, which was not associated with peripheral neuropathy. We conclude that miglustat can provide therapeutic benefits in CNS symptoms and allows stabilization of systemic disease in childhood-onset NP-C. Further follow-up is crucial to determine the long-term maintenance of these effects.

Deficiency of the carnitine transporter (OCTN2) with partial N-acetylglutamate synthase (NAGS) deficiency.

A patient with recurrent episodes of hyperammonaemia (highest ammonia level recorded 229 micromol/L, normal 9-33) leading to altered levels of consciousness was diagnosed with partial N-acetylglutamate synthase (NAGS) deficiency (9% residual activity) at age 5 years and was treated with ammonia-conjugating agents (Ucephan 250 mg/kg per day and later sodium phenylbutyrate 200-250 mg/kg per day) for 15 years. A chronically low serum carnitine level (pretreatment plasma free carnitine 4 nmol/L, normal 37 +/- 8 nmol/L; total carnitine 8 nmol/L, normal 46 +/- 10) was assumed to be secondary and was treated with supplemental carnitine (30-50 mg/kg per day). Hypoglycaemia (blood sugar 35 mg/dl, normal 70-100), cardiomegaly, and fatty liver were also noted at diagnosis. The patient died unexpectedly at age 20 years. In retrospect, it was learned that the patient had stopped his carnitine without medical consultation several weeks prior to his death. Additional molecular investigations identified two mutations (R254X and IVS3 + 1G > A) in the patient's OCTN2 (SLC22A5) gene, consistent with a diagnosis of primary carnitine deficiency due to carnitine transporter defect. R245X is a founder mutation in Southern Chinese populations. It is unknown whether the original NAGS deficiency was primary or secondary, but molecular analysis of the NAGS gene failed to identify mutations. Urea cycle enzyme expression may be affected by fatty acid suppression of an AP-1 binding site in the promoter enhancer region of the urea cycle gene. Regardless, it is clear that the NAGS abnormality has led to delay of recognition of the OCTN2 defect, and modified the clinical course in this patient.

Findings from 752,081 clinical breast examinations reported to a national screening program from 1995 through 1998.

BACKGROUND AND METHODS: Mammography programs have received extensive study, but little is known about the outcome of clinical breast examinations (CBEs) performed in community settings. Consequently, we analyzed data from the National Breast and Cervical Cancer Early Detection Program on CBEs provided to low-income women from 1995 through 1998 and determined the percentage of CBEs considered to be abnormal, suspicious for cancer; the rates of cancer detection; and the sensitivity, specificity, and positive predictive value of CBEs. RESULTS: We analyzed data from 752081 CBEs and found that 6.9% of all CBEs were coded abnormal, suspicious for cancer, and that 5.0 cancers were detected per 1000 examinations (95% confidence interval [CI] = 4.9-5.2). The values observed for sensitivity (58.8%) and specificity (93.4%) were comparable to those reported for the CBE component of clinical trials. The observed positive predictive value was 4.3%. About 74% of all records also reported mammography results. The cancer-detection rate among records reporting an abnormal CBE and normal mammography was 7.4 cancers per 1000 records (95% CI = 6. 3-8.4). When the CBE was normal but the mammography was abnormal, the rate was 42.0 cancers per 1000 records (95% CI = 39.9-44.1). When both CBE and mammography results were abnormal, the rate was 170.3 cancers per 1000 records (95% CI = 162.7-177.9). Cancer detection could not be attributed entirely to CBE or mammography on 38% of the records in the latter subset because the tests were performed on the same day. CONCLUSION: CBEs performed in community-based screening programs can detect breast cancers as effectively as CBEs performed in clinical trials and may modestly improve early-detection campaigns.

A case-control study of breast cancer and hormonal contraception in Costa Rica.

By 1981, 11% of married women in Costa Rica ages 20-49 years had used depot-medroxyprogesterone acetate (DMPA) and 58% had used oral contraceptives (OCs). Since 1977, the Costa Rican Ministry of Health has maintained a nationwide cancer registry. These circumstances provided an opportunity for a population-based, case-control study of DMPA, OCs, and breast cancer in Costa Rica. Cases were 171 women ages 25-58 years with breast cancer diagnosed between 1982 and 1984; controls were 826 women randomly chosen during a nationwide household survey. Cases and controls were interviewed with the use of a standard questionnaire covering their reproductive and contraceptive histories. Logistic regression methods were used to adjust for confounding factors. While few cases or controls had ever used DMPA, DMPA users had an elevated relative risk (RR) estimate of breast cancer of 2.6 (95% confidence limits = 1.4-4.7) compared with never users. However, no dose-response relationship was found; even the group of women who had used DMPA for less than 1 year had an elevated RR estimate (RR = 2.3; 95% confidence limits = 1.0-5.1). In contrast, OC users had no elevation in RR compared with never users (RR = 1.2; 95% confidence limits = 0.8-1.8). The results of the DMPA analysis are inconclusive. Before decisions are made on whether to continue providing this effective contraceptive method, other ongoing studies will need to confirm of refute these findings.

PIP: Depot-medroxyprogesterone acetate (DMPA) is used by approximately 2 million women world-wide. In Costa Rica, by 1981 11% of the married women had used DMPA. Although no definitive link between the use of DMPA and the development of cancer has been found, the possibility has been recognized as one of the reasons for the U.S food and Drug Administration denying approval of the drug. Since 1977, the Ministry of Health in Costa Rica has sustained a national cancer registry. The accuracy of the reporting of the registry was studied by comparing a sampling of gynecologic cancer cases in the year 1983 to the national registry. In examination of the records, an elevated relative risk of breast cancer for DMPA users was found (2.6), and an elevated relative risk for women who had even used DMPA for a short period of time (2.3). The failure to interview 1/3 of the cases, differences in detection and the misclassification of DMPA use contributed cumulatively to the belief that a positive connection between breast cancer and DMPA use could otherwise be drawn. In contrast to the association found between DMPA ever use and breast cancer, no connection was found between OC use and the incidence of breast cancer. However, due to the small number of DMPA users recorded and the void of complete and accurate recorded information, the study results remain inconclusive.

Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder. A double-blind, placebo-controlled study in patients with and without tics.

BACKGROUND: To determine the efficacy of adding haloperidol to the treatment of patients with obsessive-compulsive disorder (OCD), with or without a comorbid chronic tic disorder, who were refractory to adequate treatment with the serotonin-uptake inhibitor fluvoxamine alone. It was hypothesized that OCD patients with a concurrent chronic tic disorder would preferentially respond to this treatment. METHODS: Sixty-two patients with a primary DSM-III-R diagnosis of OCD received placebo fluvoxamine for 1 week, followed by 8 weeks of active fluvoxamine. Thirty-four of these patients were refractory to fluvoxamine and were randomized in a double-blind fashion to 4 weeks of treatment with either haloperidol (n = 17) or placebo (n = 17) added to ongoing fluvoxamine treatment. The placebo-treated group included five women and 12 men, six inpatients and 11 outpatients, and eight patients with a comorbid chronic tic disorder. The haloperidol-treated group consisted of two women and 15 men, three inpatients and 14 outpatients, and seven patients with a comorbid chronic tic disorder. All 34 patients completed the entire study. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Clinical Global Impression scale were the principal measures of treatment outcome. RESULTS: Haloperidol addition was significantly better than placebo in reducing the severity of obsessive-compulsive symptoms as measured by the Y-BOCS. Eleven of 17 patients responded to the haloperidol, compared with none of 17 patients given placebo. Eight of eight patients with comorbid chronic tic disorders, such as Tourette's disorder, responded to double-blind haloperidol addition to ongoing fluvoxamine treatment. Haloperidol addition was of little benefit in treating OCD patients without tics. Fluvoxamine blood levels were not related to treatment response. CONCLUSIONS: The results of this study suggest that OCD patients with a comorbid chronic tic disorder constitute a clinically meaningful subtype of OCD that might require conjoint serotonin-uptake inhibitor/neuroleptic therapy for effective symptom reduction.

Patterns and characteristics of repeat mammography among women 50 years and older.

Whereas efforts encouraging women to obtain initial mammograms are laudable, the importance of returning for subsequent routine mammograms cannot be minimized. The purpose of this study was to measure the timing, patterns, and characteristics of repeat screening mammography over time in a defined population of health maintenance organization members for whom mammography was a fully covered benefit. We identified all women ages 50-74 years who were enrolled in a southeastern Michigan health maintenance organization, assigned to a large medical group, and received at least one screening mammogram with a normal result between January 1, 1989 and December 31, 1996. Using administrative and radiology data, we calculated the proportion of women who received a subsequent mammogram within 2 years and the time to subsequent screening, both overall and stratified by demographic characteristics. We also examined screening patterns over a 5-year period. Of the 8749 women included in this study, 66.0% [95% confidence interval (CI), 65.0-67.0%] were subsequently screened within 2 years. We found slightly higher rates among Caucasians and married women. The proportion of women who received repeat mammography increased with estimated household income [9.5% difference between the highest and lowest categories (95% CI, 6.5-12.5%)]. The median time to subsequent screening was 17.7 months, and the probability of repeat screening was higher for women whose initial mammogram was between January 1992 and December 1994 compared to those receiving an initial mammogram between January 1989 and December 1991 (9.6% difference; 95% CI, 7.5-11.7%). Repeat mammography has improved over time; however, socioeconomic status could contribute to longer-than-intended intervals between screening when translated into real-world clinical practice. In a setting where most physicians recommended annual screening, we found that the median time to subsequent screening was delayed by 6 months. If annual mammography is the goal, recommendations should be made with the understanding of how the timing of repeat screening occurs in clinical practice.

Antimetastatic efficacy of adjuvant gemcitabine in a pancreatic cancer orthotopic model.

Gemcitabine is a promising new agent that has been recently studied for palliation of advanced (stage IV) unresectable pancreatic cancer. We hypothesized that adjuvant gemcitabine would reduce recurrence and metastases following surgical resection of pancreatic cancer. To test this hypothesis, we evaluated gemcitabine on a green fluorescent protein (GFP) transductant of the human pancreatic cancer cell line BxPC-3 (BxPC-3-GFP) using surgical orthotopic implantation (SOI) in nude mice. GFP enabled high resolution fluorescent visualization of primary and metastatic growth. Five weeks after SOI, the mice were randomized into three groups: Group I received exploratory laparotomy only. Group II underwent surgical resection of the pancreatic tumor without further treatment. Group III underwent tumor resection followed by adjuvant treatment with gemcitabine, 100 mg/kg every three days for a total of four doses, starting two days after resection. The mice were sacrificed at thirteen weeks following implantation and the presence and location of recurrent tumor was recorded. Gemcitabine reduced the recurrence rate to 28.6% compared to 70.6% with resection only (P = 0.02) and reduced metastatic events 58% in the adjuvant group compared to resection only. This study, demonstrating that gemcitabine is effective as adjuvant chemotherapy post-pancreatectomy, suggests this new indication of the drug clinically.

Agreement of self-reported ovarian number following gynecologic surgery with medical record reports.

In case-control studies of breast cancer, cardiovascular disease, and osteoporosis, a woman's ovarian function may be considered as a main exposure, confounding factor, or effect modifier. To evaluate the agreement between self-reported ovarian number following ovarian surgery for nonmalignant disease and medical record reports, we analyzed data from a population-based case-control study, the Cancer and Steroid Hormone Study. Reports on ovarian number after the most recent surgery for a who had been diagnosed with breast cancer and 496 control subjects. We then calculated agreement rates by comparing the number of ovaries indicated by the medical record with the number reported by the woman. Agreement rates on the presence or absence of ovaries exceeded 90% for both case and control subjects. Agreement rates on exact ovarian number exceeded 84% for both groups. Women who had been diagnosed with breast cancer had slightly higher agreement rates than did control women for both presence or absence of ovaries and exact ovarian number. Our data suggest that investigators can rely on self-reported ovarian number as an accurate measure of actual ovarian number in women who have had surgery for nonmalignant conditions.

A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer.

Estrogen replacement therapy (ERT) has not been associated with epithelial ovarian cancer in most reported epidemiologic studies that have looked for an association. Some studies may have found weak statistically nonsignificant associations because the number of cases or number of women who reported estrogen use was small. We performed a meta-analysis of data from 15 case-control studies that provided data on ERT and risk of epithelial ovarian cancer. The 15 combined studies were statistically heterogeneous (chi(2) (14) = 26. 3, P < 0.05) in terms of the effect they found. When we combined these studies using a random effects model, we did not find a significant association of ERT with ovarian cancer (odds ratio = 1.1, 95% confidence interval = 0.9-1.3). There was no clear evidence of a dose-response relation with increasing duration of estrogen use in a subset of five studies that reported estrogen use by duration (overall slope = 0.0012, 95% confidence interval = -0.0055 to 0. 0080). The influences of statistical outliers, study design (hospital or clinic controls vs. community controls), and location (U.S. and Canada vs. Europe and Australia) were examined. The odds ratio was 1.3 (95% confidence interval = 1.0-1.6) in the relatively homogeneous subset of four U.S. case-control studies with community controls, but we cannot rule out the possibility of uncontrolled confounding. The odds ratios for estrogen use for other subgroups defined by geographic location and type of control group were not significantly different from one.

Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer.

To quantify the effects of cumulative months of pregnancy, breast feeding, and oral contraceptive use on the risk of developing epithelial ovarian cancer, the authors used data collected for the Cancer and Steroid Hormone Study--a multicenter, population-based, case-control study. Detailed reproductive histories were obtained from 436 women aged 20-54 with epithelial ovarian cancer newly diagnosed between December 1980 and December 1982, and from 3833 women aged 20-54 selected at random from the same geographic areas. Estimated relative risks of epithelial ovarian cancer were 0.6 (95% confidence interval (CI) 0.5-0.8) for women who had ever been pregnant, 0.6 (95% CI 0.5-0.8) for women who had ever breast fed, and 0.5 (95% CI 0.5-0.7) for women who had ever used oral contraceptives. Logistic regression analysis revealed a strong trend in decreasing risk of epithelial ovarian cancer with increasing cumulative months of pregnancy; this effect was less pronounced in women aged 50-54 than in younger women. In contrast, a marked reduction in risk was associated with ever having breast fed or used oral contraceptives, while the decrease in risk from additional months of either of these exposures was less than that for pregnancy.

The relationship between body mass and breast cancer among women enrolled in the Cancer and Steroid Hormone Study.

We examined the relationship between body mass [weight (kg)/height (m)2] and breast cancer using data from the Cancer and Steroid Hormone Study. The study compared 4323 women aged 20-54 years with newly diagnosed breast cancer identified through population-based tumor registries with 4358 women randomly selected from the general population of the same geographic areas. Among naturally menopausal women, risk of breast cancer increased with increasing body mass index (BMI); those severely overweight (BMI greater than or equal to 32.30) had nearly 3-fold higher risk of breast cancer compared with women in the leanest category (BMI less than 20.00). This positive association appeared stronger with increasing years since menopause and in women who had ever used estrogen replacement therapy. A positive association between body mass and breast cancer risk also was observed among premenopausal women; however, risk estimates were substantially lower. Substantial weight gain from adolescence to adulthood was a more important risk factor than lifelong obesity. Prevalence of obesity increases with age; our results suggest that interventions that prevent this trend could have an important effect on breast cancer risk, especially during the menopausal years.