Implementing constructed wetlands for nutrient reduction at watershed scale: Opportunity to link models and real-world execution.

The negative effects of nutrient pollution in streams, rivers, and downstream waterbodies remain widespread global problems. Understanding the cost-effectiveness of different strategies for mitigating nutrient pollution is critical to making informed decisions and defining expectations that best utilize limited resources, which is a research priority for the US Environmental Protection Agency. To this end, we modeled nutrient management practices including residue management, cover crops, filter strips, grassed waterways, constructed wetlands, and reducing fertilizer in the upper East Fork of the Little Miami River, an 892 km2 watershed in southwestern Ohio, United States. The watershed is 64% agriculture with 422 km2 of row crops contributing an estimated 71% of the system's nutrient load. The six practices were modeled to treat row crop area, and among them, constructed wetlands ranked highest for their low costs per kilogram of nutrient removed. To meet a 42% phosphorus (P) reduction target for row crops, the model results suggested that the runoff from 85.5% of the row crop area would need to be treated by the equivalent of 3.61 km2 of constructed wetlands at an estimated cost of US$2.4 million annually (or US$48.5 million over a 20-year life cycle). This prompted a series of projects designed to understand the feasibility (defined in terms of build, treatment, and cost potential) of retrofitting the system with the necessary extent of constructed wetlands. The practicalities of building this wetland coverage into the system, while leading to innovation in unit-level design, has highlighted the difficulty of achieving the nutrient reduction target with wetlands alone. Approximately US$1.2 million have been spent on constructing 0.032 km2 of wetlands thus far and a feasibility analysis suggests a cost of US$38 million for an additional 0.409 km2. However, the combined expenditures would only achieve an estimated 13% of the required treatment. The results highlight the potential effectiveness of innovative design strategies for nutrient reduction and the importance of considering realistic field-scale build opportunities, which include accounting for acceptance among landowners, in watershed-scale nutrient reduction simulations using constructed wetlands.

Co-designing a Canadian adaptation of a lifestyle-oriented intervention aimed to improve daily functioning of individuals living with chronic pain: a multi-method study protocol of REVEAL(OT) Canada.

Background: Living with chronic pain (CP) often implies major lifestyle changes, including modifications of daily routines and work. Surprisingly, few validated and effective interventions specifically target functional outcomes in this population. Redesign your Everyday Activities and Lifestyle with Occupational Therapy [REVEAL(OT)] is a lifestyle-oriented intervention led by occupational therapists that directly targets the daily functional challenges of living with CP. The intervention was initially developed and studied as an add-on to standard treatment delivered by Danish multidisciplinary specialized pain clinics. Adapting, implementing, and evaluating REVEAL(OT) within the Canadian healthcare system will contribute to broadening the scope of treatments offered in specialized pain clinics that do not yet include occupational therapy. Objective: The proposed study aims to define and refine REVEAL(OT)/CA with partners (authors of original intervention, people with lived experience, clinicians, managers). Methods: This participatory action research will use a multi-method design and follow the ORBIT model for developing behavioral treatments for chronic diseases. A process of co-construction with partners and an advisory committee will take place in two Montreal specialized pain clinics. It consists of two related work packages (WPs). In WP1, a first series of focus groups with partners (n = 86) and workshops with the advisory committee will be conducted to co-develop the hypothetical pathway describing intervention components and their potential mechanisms of action on targeted outcomes, as well as the first version of the adapted intervention manual. WP2 will co-refine REVEAL(OT)/CA by exploring its acceptability, feasibility and mechanisms of action through intervention deliveries (at least twice in each of two specialized pain clinics; n ≥ 60 patients) and focus groups and/or individual interviews with participating patients and partners. At the end of this study, the intervention manual will be generated both in French and English. Discussion: This study will set the stage for subsequent implementation and effectiveness assessment projects and be an important step towards the deployment of interventions aiming to improve engagement in meaningful daily activities among adults living with CP. Registration: OSF Registries, osf.io/8gksa. Registered 3 August 2023, https://osf.io/8gksa.

Occupational balance as a component in weight loss interventions.

BACKGROUND: Obesity can limit occupational participation because of physical and mental barriers. Weight loss programmes emphasizing dietary and physical activity may lower body weight; however, mental barriers and sustainable weight loss seemed to be challenged. Weight loss influences daily patterns and structure of occupations and finding a balance in daily life during the weight loss process might improve sustainable weight loss. AIM: To explore if and how health professionals conducting weight loss programmes in Danish municipalities address elements related to occupational balance in the daily life of citizens with obesity. MATERIAL AND METHODS: Twenty individual interviews with health professionals from Danish municipalities were conducted and analysed. RESULTS: (1) Helping participants find the time and energy to lose weight, (2) Emphasizing small steps for sustainable changes and (3) Utilizing the citizen's life experience for direction. CONCLUSION: Elements of occupational balance might be addressed by the participants, however values and meaningfulness regarding occupations seem to be missing. Integrating occupational balance in weight loss programmes could enable health professionals to understand and address sustainable weight loss. SIGNIFICANCE: Occupational therapists may be ideally suited to support citizens with obesity to sustain weight loss by supporting a balanced life focussing on meaningfulness and values in occupations.

Modeling Anthropogenic and Environmental Influences on Freshwater Harmful Algal Bloom Development Detected by MERIS Over the Central United States.

Human and ecological health have been threatened by the increase of cyanobacteria harmful algal blooms (cyanoHABs) in freshwater systems. Successful mitigation of this risk requires understanding the factors driving cyanoHABs at a broad scale. To inform management priorities and decisions, we employed random forest modeling to identify major cyanoHAB drivers in 369 freshwater lakes distributed across 15 upper Midwest states during the 2011 bloom season (July-October). We used Cyanobacteria Index (CI_cyano)-A remotely sensed product derived from the MEdium Resolution Imaging Spectrometer (MERIS) aboard the European Space Agency's Envisat satellite-as the response variable to obtain variable importance metrics for 75 landscape and lake physiographic predictor variables. Lakes were stratified into high and low elevation categories to further focus CI_cyano variable importance identification by anthropogenic and natural influences. "High elevation" watershed land cover (LC) was primarily forest or natural vegetation, compared with "low elevation" watersheds LC dominated by anthropogenic landscapes (e.g., agriculture and municipalities). We used the top ranked 25 Random Forest variables to create a classification and regression tree (CART) for both low and high elevation lake designations to identify variable thresholds for possible management mitigation. Mean CI_cyano was 3 times larger for "low elevation" lakes than for "high elevation" lakes, with both mean values exceeding the "High" World Health Organization recreational guidance/action level threshold for cyanobacteria (100,000 cells/mL). Agrarian-related variables were prominent across all 369 lakes and low elevation lakes. High elevation lakes showed more influence of lakeside LC than for the low elevation lakes.

Managers attitude towards implementing workplace health promotion programmes to employees in eldercare: a cross-sectional study.

Objectives: To determine the attitudes of eldercare services managers to the potential health benefits of workplace health promotion programmes (WHPPs), including physical exercise during working hours and the feasibility of implementing a WHPP at the workplace. Study design: A cross-sectional study. Methods: Respondents filled out a 14-item questionnaire on attitudes towards the potential health benefits of WHPPs and the feasibility of implementing WHPPs. Differences between groups were analysed using the Kruskal-Wallis test. The significance level was set to p â€‹= â€‹0.05. Bonferroni's correction was used in the setting of multiple comparisons. A content analysis was performed exploring answers provided in the optional comment section in the questionnaire. Results: 695 eldercare services managers in Denmark were contacted by email, 393 replied, and 382 respondents were included in the analysis (54.7%). The survey revealed that 89.8% of the respondents believed that WHPPs would increase health, 89.6% believed that it would increase well-being and 87.6% believed that WHPPs would increase workability among workers. 87.7% expressed a willingness towards implementing WHPPs and believed 'it to be a good idea'. Respondents with a negative attitude to the feasibility of implementing WHPPs, were more likely to hold negative attitudes to the potential health benefits of WHPPs (p â€‹< â€‹0.001). Organisational issues were the most frequently stated barrier to implementation. Conclusions: The majority of eldercare managers expressed a positive attitude to the benefits of WHPPs and their implementation. Addressing organisational issues and ensuring management support in the planning stage of a WHPP is highly important.

Enhancing a Client-Centred Practice with the Canadian Occupational Performance Measure.

BACKGROUND: The active participation of clients is an important aspect of rehabilitation quality as conceptualized in client-centred practice (CCP). A recommended outcome measure for enhancing CCP is the Canadian Occupational Performance Measure (COPM). However, the relationship between COPM use and CCP enhancement has not been documented. AIM: The aim of this study was to examine whether the use of the COPM enhanced CCP. METHODS: We performed a scoping review in five steps: (1) identifying a search strategy with inclusion and exclusion criteria; (2) screening relevant databases for published and unpublished studies by using selected keywords and by manually scrutinizing reference lists; (3) agreeing on eligible papers between authors in terms of inclusion and exclusion criteria; (4) charting included data; and (5) analysing data using qualitative content analysis. RESULTS: Twelve studies were included in the review. The results indicated enhanced CCP in two themes when using the COPM. These themes appeared to influence each other; therefore, the first theme, Conditions for enhancing CCP when using the COPM, represented the circumstances needed for the second theme, Enhancing CCP when using the COPM, to be fulfilled. CONCLUSION: The use of the COPM seems to enhance CCP if certain conditions are present.

Estimating wetland connectivity to streams in the Prairie Pothole Region: an isotopic and remote sensing approach.

Understanding hydrologic connectivity between wetlands and perennial streams is critical to understanding the reliance of stream flow on inputs from wetlands. We used the isotopic evaporation signal in water and remote sensing to examine wetland-stream hydrologic connectivity within the Pipestem Creek watershed, North Dakota, a watershed dominated by prairie-pothole wetlands. Pipestem Creek exhibited an evaporated-water signal that had approximately half the isotopic-enrichment signal found in most evaporatively enriched prairie-pothole wetlands. Groundwater adjacent to Pipestem Creek had isotopic values that indicated recharge from winter precipitation and had no significant evaporative enrichment, indicating that enriched surface water did not contribute significantly to groundwater discharging into Pipestem Creek. The estimated surface-water area necessary to generate the evaporation signal within Pipestem Creek was highly dynamic, varied primarily with the amount of discharge, and was typically greater than the immediate Pipestem Creek surface-water area, indicating that surficial flow from wetlands contributed to stream flow throughout the summer. We propose a dynamic range of spilling thresholds for prairie-pothole wetlands across the watershed allowing for wetland inputs even during low flow periods. Combining Landsat estimates with the isotopic approach allowed determination of potential (Landsat) and actual (isotope) contributing areas in wetland-dominated systems. This combined approach can give insights into the changes in location and magnitude of surface water and groundwater pathways over time. This approach can be used in other areas where evaporation from wetlands results in a sufficient evaporative isotopic signal.

Unaltered neuronal and glial counts in animal models of magnetic seizure therapy and electroconvulsive therapy.

Anatomical evidence of brain damage from electroconvulsive therapy (ECT) is lacking; but there are no modern stereological studies in primates documenting its safety. Magnetic seizure therapy (MST) is under development as a less invasive form of convulsive therapy, and there is only one prior report on its anatomical effects. We discerned no histological lesions in the brains of higher mammals subjected to electroconvulsive shock (ECS) or MST, under conditions that model closely those used in humans. We sought to extend these findings by determining whether these interventions affected the number of neurons or glia in the frontal cortex or hippocampus. Twenty-four animals received 6 weeks of ECS, MST, or anesthesia alone, 4 days per week. After perfusion fixation, numbers of neurons and glia in frontal cortex and hippocampus were determined by unbiased stereological methods. We found no effect of either intervention on volumes or total number or numerical density of neurons or glia in hippocampus, frontal cortex, or subregions of these structures. Induction of seizures in a rigorous model of human ECT and MST therapy does not cause a change in the number of neurons or glia in potentially vulnerable regions of brain. This study, while limited to young, healthy, adult subjects, provides further evidence that ECT and MST, when appropriately applied, do not cause structural damage to the brain.

Hippocampal neuron and glial cell numbers in Parkinson's disease--a stereological study.

Hippocampal atrophy and neuron loss are early and reproducible findings in Alzheimer's disease, and recent magnetic resonance imaging studies indicate that hippocampal atrophy may also be present in Parkinson's disease (PD). To determine whether or not cell loss occurs in PD, we estimated the total neuron and glial cell numbers as well as the total volume unilaterally in the hippocampi of eight demented PD patients and eight control subjects. Cell numbers were estimated in the neuron-containing layers of CA1, CA2-(3), CA4, the dentate gyrus, and subiculum using the optical-fractionator technique. The Cavalieri method was used to estimate the volume of the total hippocampus and its subregions. We did not find significant differences in cell numbers or volumes in PD brains when compared with control subjects. Our results thus indicate that hippocampal atrophy and cell loss are not necessarily involved in the memory impairment and dementia observed in PD.

Neurons of a limited subthalamic area mediate elevations in cortical cerebral blood flow evoked by hypoxia and excitation of neurons of the rostral ventrolateral medulla.

Sympathoexcitatory reticulospinal neurons of the rostral ventrolateral medulla (RVLM) are oxygen detectors excited by hypoxia to globally elevate regional cerebral blood flow (rCBF). The projection, which accounts for >50% of hypoxic cerebral vasodilation, relays through the medullary vasodilator area (MCVA). However, there are no direct cortical projections from the RVLM/MCVA, suggesting a relay that diffusely innervates cortex and possibly originates in thalamic nuclei. Systematic mapping by electrical microstimulation of the thalamus and subthalamus revealed that elevations in rCBF were elicited only from a limited area, which encompassed medial pole of zona incerta, Forel's field, and prerubral zone. Stimulation (10 sec train) at an active site increased rCBF by 25 +/- 6%. Excitation of local neurons with kainic acid mimicked effects of electrical stimulation by increasing rCBF. Stimulation of the subthalamic cerebrovasodilator area (SVA) with single pulses (0.5 msec; 80 microA) triggered cortical EEG burst-CBF wave complexes with latency 24 +/- 5 msec, which were similar in shape to complexes evoked from the MCVA. Selective bilateral lesioning of the SVA neurons (ibotenic acid, 2 microg, 200 nl) blocked the vasodilation elicited from the MCVA and attenuated hypoxic cerebrovasodilation by 52 +/- 12% (p < 0.05), whereas hypercarbic vasodilation remained preserved. Lesioning of the vasodilator site in the basal forebrain failed to modify SVA-evoked rCBF increase. We conclude that (1) excitation of intrinsic neurons of functionally restricted region of subthalamus elevates rCBF, (2) these neurons relay signals from the MCVA, which elevate rCBF in response to hypoxia, and (3) the SVA is a functionally important site conveying vasodilator signal from the medulla to the telencephalon.

The medullary cerebrovascular vasodilator area mediates cerebrovascular vasodilation and electroencephalogram synchronization elicited from cerebellar fastigial nucleus in Sprague-Dawley rats.

We investigated whether the medullary cerebrovasodilator area (MCVA), a region of ventral medulla mediating elevations of regional cerebral blood flow (rCBF) and electroencephalogram (EEG) synchronization elicited in cerebral cortex from stimulation of reticulospinal neurons of rostral ventrolateral medulla (RVLM), also mediates comparable responses from the cerebellar fastigial nucleus (FN). In spinalized rats, electrical stimulation of MCVA, RVLM or FN elevated rCBF and synchronized the EEG. The FN-evoked responses were significantly attenuated or blocked by bilateral lesions of MCVA. The MCVA is a novel region of medullary reticular formation mediating actions of medullary and cerebellar centers on rCBF and EEG to link visceral centers of brainstem and cerebral cortex.

Characteristics and outcomes of a home and community-based neurorehabilitation programme.

The potential clinical and financial advantages of providing neurorehabilitation directly in patients' homes and communities have recently been discussed. However, the specific characteristics and outcomes of a coordinated, interdisciplinary, home-based programme does not currently exist in the rehabilitation literature. The present paper presents patient demographics, type and intensity of services provided, satisfaction measures, and clinical outcomes for 77 brain injured individuals in an attempt to begin to define and evaluate this new level of care. Additionally, the challenges of conducting home-based rehabilitation, and needs for further research are discussed.

Process and product development in the manufacturing of molecular therapeutics.

In the development of molecular therapies, a great deal of attention has focused on tissue targets, gene delivery vectors, and expression cassettes. In order to become an approved therapy, however, a molecular therapeutic has to pass down the same product registration pathway as any other biological product. Moving from research into industrial production requires careful attention to regulatory, manufacturing and quality concerns. Early work on developing and characterizing robust and scaleable manufacturing processes will ultimately be rewarded by ease of implementation as the product is successful in clinical trials. Regulatory agencies require solid process and product characterization studies to demonstrate control and understanding of the molecular therapeutic. As the gene therapy industry matures, standards will continue to rise, creating an industry that is capable of producing safe, high-quality and effective therapies for many of the world's most difficult disease targets.

Process and product development in the manufacturing of molecular therapeutics.

In the development of molecular therapies, a great deal of attention has focused on tissue targets, gene delivery vectors, and expression cassettes. In order to become an approved therapy, however, a molecular therapeutic has to pass down the same product registration pathway as any other biological product. Moving from research into industrial production requires careful attention to regulatory, manufacturing and quality concerns. Early work on developing and characterizing robust and scaleable manufacturing processes will ultimately be rewarded by ease of implementation as the product is successful in clinical trials. Regulatory agencies require solid process and product characterization studies to demonstrate control and understanding of the molecular therapeutic. As the gene therapy industry matures, standards will continue to rise, creating an industry that is capable of producing safe, high-quality and effective therapies for many of the world's most difficult disease targets.

Consequences of the delayed diagnosis of ataxia-telangiectasia.

OBJECTIVES: Ataxia-telangiectasia (AT) is a rare, autosomal recessive neurodegenerative disorder in which the diagnosis is obvious when ataxia and telangiectasia are both present. However, the diagnosis can be made upon the onset of ataxia and before the appearance of telangiectasia if confirmed by laboratory tests. Early diagnosis is important for genetic counseling, appropriate care, and avoidance of unnecessary tests. The purpose of this study is to identify factors responsible for delays in the diagnosis of AT. DESIGN: The records of all patients seen at the Ataxia-Telangiectasia Clinical Center from July 1, 1995 to April 1, 1997 were reviewed to determine age of onset of gait abnormality, recognition of telangiectasia, and diagnosis. RESULTS: In 48 patients with AT, who were the index cases in their respective families, the median age of diagnosis (78 months) occurred after the onset of gait abnormalities (15 months) and closely corresponded to the development of telangiectasia (72 months). In the majority of cases (34/48), telangiectasia appeared before the diagnosis was established. The most common misdiagnosis was cerebral palsy (29/48 cases). Twenty-one children (4 with AT) were born after the start of symptoms in the index case, but before the establishment of a diagnosis. CONCLUSIONS: The term AT, although a concise and memorable label for the disorder, is also a barrier to early diagnosis. We recommend the use of routine serum alpha-fetoprotein testing for all children with persistent ataxia.

Real-time measurement of electrically evoked extracellular dopamine in the striatum of freely moving rats.

The real-time measurement of electrically evoked dopamine was established in brain extracellular fluid of freely moving rats. Dopamine was monitored by fast-scan cyclic voltammetry at carbon fiber microelectrodes lowered into the striatum by means of a detachable micromanipulator. A stimulating electrode, previously implanted in the substantia nigra, was used to evoke striatal dopamine efflux. Evoked extracellular dopamine was both current and frequency dependent. When low current intensities (+/-125 microA) and frequencies (10-20 Hz) were applied, detectable levels of dopamine were elicited without a perceptible behavioral response. Reproducible concentrations of extracellular dopamine could be evoked in the same rat for at least 2 months. These concentrations, moreover, were significantly higher in freely moving rats compared with rats anesthetized with Equithesin. Analysis of measured curves for dopamine uptake and release rates revealed that anesthesia inhibits release but does not affect uptake. It is concluded that (a) fast-scan cyclic voltammetry at carbon fiber microelectrodes is a viable technique for the measurement of electrically evoked dopamine in brain extracellular fluid of freely moving rats, (b) it is possible to determine in situ rate constants for dopamine release and uptake from these temporally and spatially resolved measurements of levels of dopamine, and (c) transient changes in extracellular dopamine levels elicited by electrical stimulation are affected by anesthesia.

Pediatric traumatic brain injury rehabilitation: challenges in care delivery.

The provision of rehabilitation and long-term services to children and adolescents with traumatic brain injury is a challenge, in part related to the issues of growth and development. The needs of and the demands on the child change over time with different stages of development. This can be further complicated by the emergence of new deficits which often become apparent during transitions requiring more independent functioning. Additionally, changing models of care delivery and the need to improve efficiency and effectiveness of services present challenges for the systems providing services to these children and adolescents and their families. Communication and cooperation between and within these systems (medical and educational) must be optimal, to encourage appropriate, effective services and timely transitions.

Regional and temporal differences in real-time dopamine efflux in the nucleus accumbens during free-choice novelty.

To assess dopamine efflux during novelty-seeking behavior in rats, fast-scan cyclic voltammetry in the nucleus accumbens was combined with free-choice entry into a novel environment. Cyclic voltammograms, confirmed by in vitro testing, revealed that entry into novel, but not familiar, surroundings increased dopamine efflux in a regionally and temporally distinct pattern. Whereas dopamine failed to change in the core region of the accumbens and overlying neostriatum, an abrupt increase occurred in accumbal shell, a limbic-related area implicated in goal-directed behavior. Although the dopamine response was confined to the brief period of entry into novelty (approximately 8 s duration), a less rapid and more persistent dopamine change (> 20 s duration) occurred in the shell-core transition zone, the so-called shore. These results suggest that novelty mimics other positively reinforcing stimuli in enhancing dopamine transmission in the nucleus accumbens, but the regional and temporal heterogeneity of this effect may represent different aspects of accumbal dopamine function.

Chloroquine augments the binding of insulin to its receptor.

The effect of chloroquine on the interaction of insulin with its receptor has been investigated under both equilibrium and non-equilibrium conditions. Chloroquine was found to augment insulin binding in a pH-dependent manner between pH 6.0 and pH 8.5, with the maximum occurring at approximately pH 7.0. Analysis of the equilibrium binding data in terms of independent binding sites gave equivocal results but suggested an increase in the high-affinity component. Analysis using the negative co-operativity binding model of De Meyts, Bianco and Roth [J. Biol. Chem. (1976) 251, 1877-1888] suggested that the affinity at both high and low occupancy was increased equally. The kinetics of association of insulin with the plasma-membrane receptor indicated that, although the net rate of association increased in the presence of chloroquine, this was due to a reduction in the dissociation rate rather than an increase in the association rate. This was confirmed by direct measurement of the rates of dissociation. Dissociation was found to be distinctly biphasic, with fast and slow components. Curve fitting suggested that the decrease in dissociation rate in the presence of chloroquine was not due to a decrease in either of the two dissociation rate constants, but rather to an increase in the amount of insulin dissociating by the slow component. It was also found that the increase in dissociation rate in the presence of excess insulin, ascribed to negative co-operativity, could be accounted for by an increase in the amount of insulin dissociating by the faster pathway, rather than by an increase in the dissociation rate constant. Thus chloroquine appears to have the opposite effect to excess insulin, and evidence was found for the induction of positive co-operativity in the insulin-receptor interaction at high chloroquine concentrations. Evidence was also found for the presence of low-affinity chloroquine binding sites with binding parameters similar to the concentration dependence of the chloroquine-induced augmentation of insulin binding.

Amphetamine, cocaine, and dizocilpine enhance performance on a lever-release, conditioned avoidance response task in rats.

A lever-release version of the conditioned avoidance response (CAR) task was used to assess the behavioral effects of several psychomotor stimulants in rats. The indirect dopamine agonists, d-amphetamine (0.1 and 0.25 mg/kg) and cocaine (7.5 and 15 mg/kg), enhanced performance on this task. Both drugs increased percent avoidance responses and decreased avoidance latency. A higher dose of amphetamine (0.5 mg/kg) also decreased avoidance latency but failed to improve percent avoidance. Similar effects were seen at low (0.01 and 0.025 mg/kg) and high (0.05 mg/kg) doses of dizocilpine (MK-801), a stimulant that acts as a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors. When combined with haloperidol (0.1 mg/kg), a dopamine antagonist, amphetamine (0.25 mg/kg) and dizocilpine (0.025 mg/kg) had differential effects on the lever-release CAR task. Thus, amphetamine-haloperidol was significantly better than haloperidol alone on percent avoidance but not on avoidance latency, whereas dizocilpine-haloperidol had the opposite effect: significantly better than haloperidol alone on avoidance latency but not on percent avoidance. Taken together, these results provide further support for dopaminergic mechanisms in CAR performance but suggest an opposing glutamatergic influence.