Valid or not: A critique of Graver and Green.

Disagreements in science and medicine are not uncommon, and formal exchanges of disagreements serve a variety of valuable roles. As identified by a Nature Methods editorial entitled "The Power of Disagreement" (2016), disagreements bring attention to best practices so that differences in interpretation do not result from inferior data sets or confirmation bias, "prompting researchers to take a second look at evidence that is not in agreement with their hypothesis, rather than dismiss it as artifacts." Graver and Green published reasons why they disagree with a recent clinical case report and a decades old randomized control trial characterizing the effect of an acute 2 mg dosing of lorazepam on the Word Memory Test. In this article, we formally responded to their commentary to further clarify the reasons for our data interpretations. These two opposing views provide an excellent learning opportunity, particularly for students, demonstrating the importance of careful articulation of the rationale behind certain conclusions from different perspectives. We encourage careful review of the original articles being discussed so the neuropsychologists can read both positions and decide which interpretation of the findings they consider most sound.

Superior Verbal Memory Outcome After Stereotactic Laser Amygdalohippocampotomy.

Objective: To evaluate declarative memory outcomes in medically refractory epilepsy patients who underwent either a highly selective laser ablation of the amygdalohippocampal complex or a conventional open temporal lobe resection. Methods: Post-operative change scores were examined for verbal memory outcome in epilepsy patients who underwent stereotactic laser amygdalohippocampotomy (SLAH: n = 40) or open resection procedures (n = 40) using both reliable change index (RCI) scores and a 1-SD change metric. Results: Using RCI scores, patients undergoing open resection (12/40, 30.0%) were more likely to decline on verbal memory than those undergoing SLAH (2/40 [5.0%], p = 0.0064, Fisher's exact test). Patients with language dominant procedures were much more likely to experience a significant verbal memory decline following open resection (9/19 [47.4%]) compared to laser ablation (2/19 [10.5%], p = 0.0293, Fisher's exact test). 1 SD verbal memory decline frequently occurred in the open resection sample of language dominant temporal lobe patients with mesial temporal sclerosis (8/10 [80.0%]), although it rarely occurred in such patients after SLAH (2/14, 14.3%) (p = 0.0027, Fisher's exact test). Memory improvement occurred significantly more frequently following SLAH than after open resection. Interpretation: These findings suggest that while verbal memory function can decline after laser ablation of the amygdalohippocampal complex, it is better preserved when compared to open temporal lobe resection. Our findings also highlight that the dominant hippocampus is not uniquely responsible for verbal memory. While this is at odds with our simple and common heuristic of the hippocampus in memory, it supports the findings of non-human primate studies showing that memory depends on broader medial and lateral TL regions.

Maternal Complications and Prescription Opioid Exposure During Pregnancy: Using Marginal Structural Models.

INTRODUCTION: Prescription opioids are frequently used for pain management in pregnancy. Studies examining perinatal complications in mothers who received prescription opioids during pregnancy are still limited. OBJECTIVES: The aim of this study was to assess the association of prescription opioid use and maternal pregnancy and obstetric complications. METHODS: This retrospective cohort study with the Rhode Island (RI) Medicaid claims data linked to vital statistics throughout 2008-2015 included pregnant women aged 12-55 years with one or multiple live births. Women were excluded if they had cancer, opioid use disorder, or opioid dispensing prior to but not during pregnancy. Main outcomes included adverse pregnancy and obstetric complications. Marginal Structural Cox Models with time-varying exposure and covariates were applied to control for baseline and time-varying covariates. Analyses were conducted for outcomes that occurred 1 week after opioid exposure (primary) or within the same week as exposure (secondary). Sensitivity studies were conducted to assess the effects of different doses and individual opioids. RESULTS: Of 9823 eligible mothers, 545 (5.5%) filled one or more prescription opioid during pregnancy. Compared with those unexposed, no significant risk was observed in primary analyses, while in secondary analyses opioid-exposed mothers were associated with an increased risk of cesarean antepartum depression (HR 3.19; 95% CI 1.22-8.33), and cardiac events (HR 9.44; 95% CI 1.19-74.83). In sensitivity analyses, results are more prominent in high dose exposure and are consistent for individual opioids. CONCLUSIONS: Prescription opioid use during pregnancy is associated with an increased risk of maternal complications.

Association of Gestational Opioid Exposure and Risk of Major and Minor Congenital Malformations.

Importance: The rapid increase of opioid-related overdoses and deaths has become a public health concern in the US. Use of prescription opioids in pregnant women has increased; results from teratogenicity studies remain controversial. Objective: To evaluate the association between maternal prescription opioid use (excluding opioid use disorders) during pregnancy and the incidence of congenital malformations. Design, Setting, and Participants: This retrospective population-based cohort study evaluated linked Rhode Island Medicaid claims and vital statistics data of live births from January 1, 2008, to December 31, 2016. Data analysis was conducted from May 1, 2019, to May 31, 2020. Women who had a live birth during the study period, but no cancer or opioid use disorder, were followed up from 3 months before pregnancy to the end of pregnancy. Exposures: Data on the mother's prescription opioid exposure were obtained through pharmacy claims and exposure was defined as dispensing of at least 1 prescription opioid during the first, second, or third trimester. Main Outcomes and Measures: The primary outcome was overall major or minor congenital malformations, defined as 1 or more major or minor congenital malformation. Secondary outcomes were defined as 10 specific categories of congenital malformations classified by organ systems using International Classification of Diseases diagnosis codes. Results: Of 12 424 included pregnancies, 891 mothers (7.2%) received prescription opioids during pregnancy and 3153 infants (25.4%) were diagnosed with major or minor congenital malformations. Comparing prescription opioid exposure vs nonexposure, no excess risk was observed for major birth defects in infants with opioid exposure in trimester 1 (adjusted relative risk [aRR], 1.40; 95% CI, 0.84-2.34), and higher risks were found for overall minor birth defects in trimester 3 (aRR, 1.26; 95% CI, 1.04-1.53) and minor birth defects in the musculoskeletal system in trimester 2 (aRR, 1.50; 95% CI, 1.10-2.03) and trimester 3 (aRR, 1.65; 95% CI, 1.23-2.22). Significant dose responses in selected minor malformations and effects of specific opioids were also identified. Hydrocodone in trimester 2 (aRR, 3.01; 95% CI, 1.80-5.03) and oxycodone in trimester 3 (aRR, 2.43; 95% CI, 1.37-4.02) were associated with plagiocephaly, polydactyly, and other specified congenital deformities of the hip. Conclusions and Relevance: The findings of this study suggest a higher risk of minor congenital malformations associated with use of prenatal prescription opioids in trimester 3, which seems to be dose-dependent. Further investigation is needed to establish causality and explore the physiologic plausibility of the association.

Mood and quality of life in patients treated with brain-responsive neurostimulation: The value of earlier intervention.

OBJECTIVE: To establish whether earlier treatment using direct brain-responsive neurostimulation for medically intractable focal-onset seizures is associated with better mood and Quality of Life (QoL) compared to later treatment intervention. METHODS: Data were retrospectively analyzed from prospective clinical trials of a direct brain-responsive neurostimulator (RNS® System) for treatment of adults with medically intractable focal-onset epilepsy. Participants completed the Quality of Life in Epilepsy Inventory (QOLIE-31) yearly through 9 years of follow-up and the Beck Depression Inventory-II (BDI-II) through 2 years of follow-up. Changes in each assessment after treatment with responsive neurostimulation were calculated for patients who began treatment within 10 years of seizure onset (early) and those who began treatment 20 years or more after seizure onset (late). RESULTS: The median duration of epilepsy was 18.3 years at enrollment. At 9 years, both the early (N = 51) and late (N = 109) treatment groups experienced similar and significant reductions in the frequency of disabling seizures (73.4% and 77.8%, respectively). The early treatment patients had significant improvements in QoL and mood. However, the late treatment patients not only failed to show these improvements but also declined in the emotional QoL subscale. CONCLUSIONS: Patients treated with brain-responsive neurostimulation earlier in the course of their epilepsy show significant improvements in multiple domains of QoL and mood that are not observed in patients treated later in the course of their epilepsy despite similar efficacy in seizure reduction. Even with similar and substantial reductions in seizure frequency, the comorbidities of uncontrolled epilepsy may be less responsive to treatment when too many years have passed. The results of this study suggest that, as with resective and ablative surgery, treatment with brain-responsive neurostimulation should be delivered as early as possible in the course of medically resistant epilepsy to maximize the opportunity for improvements in mood and QoL.

Laser interstitial thermal therapy (LITT): Seizure outcomes for refractory mesial temporal lobe epilepsy.

BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive alternative with less cognitive risks compared with traditional surgery for focal drug-resistant epilepsy. OBJECTIVE: We describe seizure outcomes and complications after LITT in our cohort with intractable mesial temporal lobe epilepsy (MTLE). MATERIAL AND METHODS: We prospectively tracked Stanford's MTLE cases treated with LITT from October 2014 to October 2017. Primary endpoints were seizure outcomes by (1) Engel classification and (2) reduction in baseline seizure frequency. Secondary outcomes were postablation complications. RESULTS: A total of 30 patients underwent selective amygdalohippocampotomy via LITT. Mesial temporal sclerosis (MTS) was present in 23/30 (77%) patients. Median follow-up was 18 ±â€¯12 months (range: 6-44 months). Almost all 28/29 (97%) patients had >50% reduction, and 22/29 (76%) patients had >90% reduction in seizure frequency. Engel Class I outcome was achieved in 18/29 (62%) patients; with complete seizure freedom in 9/29 (31%) patients (Engel Class IA). Three (10%) patients have had only focal aware seizures (Engel Class 1B). Seizures only occurred with medication withdrawal in 6/29 (21%) patients (Engel Class ID). Class II was achieved by 6/29 (21%) and Class III by 5/29 (17%) patients. Complications included perioperative seizures in 10/29 (34%) and nonseizure complaints in 6/29 (21%) patients. Three (10%) patients had neurological deficits including one permanent superior quadrantanopsia, one transient trochlear, and one transient oculomotor nerve palsy. CONCLUSIONS: Overall, Engel Class I outcome was achieved in 62% of patients with MTLE, and 97% of patients achieved >50% seizure frequency reduction. Complications were largely temporary, though there was one persistent visual field deficit. Laser ablation is well-tolerated and offers marked seizure reduction for the majority of patients.

Cognitive safety of intracranial electrodes for epilepsy.

Two recent articles in Epilepsia have raised concerns about adverse cognitive effects associated with intracranial electrode implantation. However, both studies have important limitations, and their results contrast with studies that report no adverse cognitive effects of intracranial electrodes for diagnosis or neurostimulation in epilepsy. Furthermore, no data are provided on the relative safety of depth electrodes implanted along the longitudinal axis of the hippocampus vs other electrode locations or types of electrodes. Instituting changes in the use of depth electrodes based solely on these 2 studies is not clinically indicated. Further research is needed.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Better object recognition and naming outcome with MRI-guided stereotactic laser amygdalohippocampotomy for temporal lobe epilepsy.

OBJECTIVES: Patients with temporal lobe epilepsy (TLE) experience significant deficits in category-related object recognition and naming following standard surgical approaches. These deficits may result from a decoupling of core processing modules (e.g., language, visual processing, and semantic memory), due to "collateral damage" to temporal regions outside the hippocampus following open surgical approaches. We predicted that stereotactic laser amygdalohippocampotomy (SLAH) would minimize such deficits because it preserves white matter pathways and neocortical regions that are critical for these cognitive processes. METHODS: Tests of naming and recognition of common nouns (Boston Naming Test) and famous persons were compared with nonparametric analyses using exact tests between a group of 19 patients with medically intractable mesial TLE undergoing SLAH (10 dominant, 9 nondominant), and a comparable series of TLE patients undergoing standard surgical approaches (n=39) using a prospective, nonrandomized, nonblinded, parallel-group design. RESULTS: Performance declines were significantly greater for the patients with dominant TLE who were undergoing open resection versus SLAH for naming famous faces and common nouns (F=24.3, p<0.0001, η2=0.57, and F=11.2, p<0.001, η2=0.39, respectively), and for the patients with nondominant TLE undergoing open resection versus SLAH for recognizing famous faces (F=3.9, p<0.02, η2=0.19). When examined on an individual subject basis, no SLAH patients experienced any performance declines on these measures. In contrast, 32 of the 39 patients undergoing standard surgical approaches declined on one or more measures for both object types (p<0.001, Fisher's exact test). Twenty-one of 22 left (dominant) TLE patients declined on one or both naming tasks after open resection, while 11 of 17 right (nondominant) TLE patients declined on face recognition. SIGNIFICANCE: Preliminary results suggest (1) naming and recognition functions can be spared in TLE patients undergoing SLAH, and (2) the hippocampus does not appear to be an essential component of neural networks underlying name retrieval or recognition of common objects or famous faces.

Low vitamin D levels are common in patients with epilepsy.

PURPOSE: Vitamin D is important for bone health, and vitamin D deficiency may contribute to other disorders (e.g., autoimmune, infections, cancer, degenerative, diabetic, and vascular). Enzyme-inducing antiepileptic drugs have been particularly implicated for osteoporosis risk given their effects on vitamin D. We examined the prevalence of vitamin D deficiency in adult epilepsy patients. METHODS: We conducted an observational study of consecutive epilepsy patients treated by two clinicians at the Emory University Epilepsy Center from 2008 to 2011 in order to determine the frequency of low vitamin D levels and possible differential antiepileptic drug risks. Vitamin D 25-OH levels were categorized as low (<20 ng/ml), borderline (20-29 ng/ml), or normal (≥30 ng/ml). Antiepileptic drugs were categorized based on their enzyme inducing properties. Descriptive and inferential statistics were employed. RESULTS: Vitamin D levels were obtained on 596 patients with epilepsy. Mean age was 41 years (SD=14; range=18-81); 56% were women. Race/ethnicity was 55% Caucasian, 34% Black, 2% Asian, and 7% Unknown. The mean vitamin D level was 22.5 (SD=11.9; range = <4 to 98), and 45% had level <20 ng/ml. Mean vitamin D levels (F=6.48, p=.002) and frequencies of vitamin D categories (p=.002, Chi square test) differed across the antiepileptic drug groups. Vitamin D deficiency was present in 54% of enzyme-inducing and 37% of non-enzyme-inducing antiepileptic drugs groups. CONCLUSIONS: Vitamin D deficiency is common in patients with epilepsy on antiepileptic drugs. Monitoring of vitamin D should be considered as part of the routine management of patients with epilepsy.

Cortical cartography reveals political and physical maps.

Advances in functional imaging have provided noninvasive techniques to probe brain organization of multiple constructs including language and memory. Because of high overall rates of agreements with older techniques, including Wada testing and cortical stimulation mapping (CSM), some have proposed that those approaches should be largely abandoned because of their invasiveness, and replaced with noninvasive functional imaging methods. High overall agreement, however, is based largely on concordant language lateralization in series dominated by cases of typical cerebral dominance. Advocating a universal switch from Wada testing and cortical stimulation mapping to functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG) ignores the differences in specific expertise across epilepsy centers, many of which often have greater skill with one approach rather than the other, and that Wada, CSM, fMRI, and MEG protocols vary across institutions resulting in different outcomes and reliability. Specific patient characteristics also affect whether Wada or CSM might influence surgical management, making it difficult to accept broad recommendations against currently useful clinical tools. Although the development of noninvasive techniques has diminished the frequency of more invasive approaches, advocating their use to replace Wada testing and CSM across all epilepsy surgery programs without consideration of the different skills, protocols, and expertise at any given center site is ill-advised.

The effect of epilepsy surgery on caregiver quality of life.

PURPOSE: Epilepsy surgery has been shown to improve patient quality of life (QOL). Little is known about its effect on caregiver QOL. METHODS: The study population comprised of 26 persons with epilepsy (PWE) who underwent long term video EEG monitoring at Massachusetts General Hospital for presurgical evaluation along with 16 caregivers. The PWE completed epilepsy directed QOL (QOLIE-31) and psychological (Beck depression-BDI and anxiety inventory-BAI) questionnaires before and after surgery. Their participating caregivers completed generic health related QOL (SF36v2) and disease burden (Zarit caregiver burden inventory-ZCBI) questionnaires before and after surgery. Demographic data for all participants and disease/surgery related data for the PWE were collected. Statistical analysis was performed to compare PWE and caregiver QOL before and after surgery. RESULTS: Mean patient age was 37 years. Most (77%) suffered from symptomatic partial epilepsy for approximately 18 years prior to surgery, averaging 4 seizures per month and 2.2 antiepileptic drugs (AEDs). 78% of them underwent an anterior temporal lobectomy and the rest extra-temporal resections. On follow up at approximately 9 months, 69% had a surgical outcome of Engel class I, 23% of class II and 8% class IV. Postoperatively, the PWE remained on average on 1.9 AEDs. There was a statistically significant improvement for both the aggregate QOLIE-31 score and all its subscales (except for medication effects) as well as the BAI scores. 96% of the PWE felt that the decision to go through surgery was worthwhile. Mean caregivers age was 47 years. Half of them were spouses to the PWE and the majority of the rest their parents. 50% of them stated that their overall time devoted to patient's care decreased after surgery and 50% that it remained unchanged. The mental component scale (SF36v2, MCS) of caregiver QOL showed statistically significant improvement. ZCBI score and the physical component scale of their QOL (SF36v2, PCS) did not significantly vary before and after surgery. 75% of caregivers deemed their QOL better post surgery vs 19% similar. 94% of the caregivers felt that the decision to go through surgery was worthwhile. CONCLUSIONS: Successful epilepsy surgery has a positive impact not only to patient QOL but also to their caregiver. To the best of our knowledge, this is the first pilot study to systematically address the impact of epilepsy surgery on caregivers providing additional support to epilepsy surgery as the optimal treatment modality in carefully selected patients. These findings call for further investigation on the caregiver quality of life in epilepsy and for its inclusion in the treatment plan and quality indicators for epilepsy surgery.

Famous face identification in temporal lobe epilepsy: support for a multimodal integration model of semantic memory.

This study aims to demonstrate that the left and right anterior temporal lobes (ATLs) perform critical but unique roles in famous face identification, with damage to either leading to differing deficit patterns reflecting decreased access to lexical or semantic concepts but not their degradation. Famous face identification was studied in 22 presurgical and 14 postsurgical temporal lobe epilepsy (TLE) patients and 20 healthy comparison subjects using free recall and multiple choice (MC) paradigms. Right TLE patients exhibited presurgical deficits in famous face recognition, and postsurgical deficits in both famous face recognition and familiarity judgments. However, they did not exhibit any problems with naming before or after surgery. In contrast, left TLE patients demonstrated both pre- and postsurgical deficits in famous face naming but no significant deficits in recognition or familiarity. Double dissociations in performance between groups were alleviated by altering task demands. Postsurgical right TLE patients provided with MC options correctly identified greater than 70% of famous faces they initially rated as unfamiliar. Left TLE patients accurately chose the name for nearly all famous faces they recognized (based on their verbal description) but initially failed to name, although they tended to rapidly lose access to this name. We believe alterations in task demands activate alternative routes to semantic and lexical networks, demonstrating that unique pathways to such stored information exist, and suggesting a different role for each ATL in identifying visually presented famous faces. The right ATL appears to play a fundamental role in accessing semantic information from a visual route, with the left ATL serving to link semantic information to the language system to produce a specific name. These findings challenge several assumptions underlying amodal models of semantic memory, and provide support for the integrated multimodal theories of semantic memory and a distributed representation of concepts.

Diagnostic utility of Wada Memory Asymmetries: sensitivity, specificity, and likelihood ratio characterization.

The authors used logistic regression, dichotomous and multiple level likelihood ratios, and receiver operating characteristic (ROC) analyses to examine Wada Memory Asymmetries (WMAs) in 324 patients who subsequently underwent temporal lobe (TL) surgery (left TL surgery = 172; right TL surgery = 152) using the Medical College of Georgia Wada protocol. Logistic regression correctly classified 84% of left TL patients and 77% of right TL patients using WMA. Corresponding dichotomous likelihood ratios (LRs) were: LR+ = 3.64; LR- = 0.21. The area under the curve using ROC was similarly highly significant (.886, standard error = .018, p < .001). When classifying patients using multiple level LRs, 40 left TL patients (23.3%) obtained asymmetry scores greater than +4, whereas no right TL patients obtained asymmetry scores in this range. No left TL patients obtained a WMA of -8 or less, although 12 right TL patients (7.9%) obtained a difference score of -8. Multiple level LRs indicate impressive diagnostic sensitivity for certain WMA ranges, greatly increasing the probability of undergoing either left or right TL surgery depending on WMA magnitude.

Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. The committee evaluated the available evidence according to a structured literature review and classification of relevant articles. For WWE who are taking antiepileptic drugs (AEDs), there is probably no substantially increased risk (>2 times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (>1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. WWE should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84-92%) of remaining seizure-free during pregnancy. WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery.

Teratogenicity of antiepileptic medications.

Antiepileptic drugs (AEDs) are frequently used to treat several conditions that are common in women of childbearing age, including epilepsy, headaches, and mood disorders. Moreover, as in the case of epilepsy and severe psychiatric disease, clinicians frequently do not have the option of stopping these medications or switching to another class of drugs. Overall, AEDs have been associated with an increased risk of major congenital malformations, minor anomalies, specific congenital syndromes, and developmental disorders seen in childhood. However, the differential effects of individual AEDs remain uncertain. Data are accumulating which strongly suggest that these risks are highest in patients receiving polypharmacy and valproate. There is also modest evidence to suggest an increased risk for phenobarbital. While other older AEDs appear to carry some teratogenic risk, there is not adequate evidence to further stratify their risk. Clinical and basic science research regarding newer AEDs suggests equivalent, if not safer, profiles compared with older AEDs, but these data are inconclusive. Management of women with epilepsy should include a discussion of these risks, prophylactic treatment with folic acid, and the minimal use of polypharmacy and valproate needed to maintain optimum seizure control.