[Prescribed and dispensed in the third trimester of pregnancy drugs: What practices and risks?]. / Médicaments prescrits et dispensés au cours du troisième trimestre de grossesse : quelles pratiques et quels risques ?

OBJECTIVE: The aim of the study was to describe the prescribing of drugs to pregnant women during the third trimester of pregnancy. PATIENTS AND METHODS: The retrospective analysis is interested by pregnant women from August 2009 to April 2011, living in Franche-Comté. The used data are recorded in the database of the French Health Insurance Service. Drugs prescribing were analyzed and classified according to three categories: drugs that are contraindicated, not recommended drugs and drugs that are used. This classification is based on two databases: the Summaries of Product Characteristics of Vidal 2010 and data from the National Security Agency of Medicines. The potential exposure of patients was pointed out. RESULTS: On 15,027 patients, 80% had a prescription. Six percent of prescriptions containing drugs not recommended and 1% drugs that contraindicated. Therapeutic classes identified are analgesics, anti-infective drugs and medicines supplementing with vitamins and minerals. Contraindicated drugs (10%) are NSAIDs, rubella vaccine, cyclins and ACE inhibitors and ARBs. Approximately 2.7% of women were potentially exposed to these drugs. DISCUSSION AND CONCLUSION: Despite the recommendations of the ANSM, some drugs that are contraindicated are prescribed for pregnant women in their third trimester of pregnancy. In the absence of studies, the decision must be made on a case by case basis by assessing the risk-benefit ratio. Particular care is to bring about the drugs taken in self-medication. Information and advice are key steps to avoid incidents.

[Pharmacists' interventions conducted by hospital pharmacists on psychotropic drugs pharmacotherapy]. / Interventions pharmaceutiques émises par les pharmaciens sur les médicaments psychotropes.

INTRODUCTION: The French Society of Clinical Pharmacy (SFPC) through the special interest group "standardization and optimization of clinical pharmacy activities" stated that the study of pharmacists' interventions (PIs) conducted during prescription analysis was a priority. The SFPC developed an internet website named Act-IP(®) (http://www.sfpc.eu/fr/) where French speaking pharmacists were able to document PIs using a normalized codification. The objective of this study was to analyze medication-related problems linked to psychotropic drugs in hospital and to investigate PIs performed during prescription analysis. MATERIALS AND METHODS: This is a multicenter, retrospective, observational study using PIs involving psychotropic medications recorded between September 2006 and February 2009 on the Act-IP(®) website. RESULTS: Four thousand six hundred and twenty PIs recorded by 165 pharmacists in 57 hospitals were related to psychotropic drugs. Patients concerned by these drug-related problems were 64 years old on average. Seven categories of medication-related problems represented more than 69% of PIs (1.1-Non Conformity of the drug choice compared to the formulary; 4.1 Supratherapeutic dose; 5.3 Therapeutic redundancy; 6.2 Drug interaction (all levels of severity); 7.0 Adverse drug reaction; 8.3 Inappropriate drug form; 8.5 Inappropriate timing of administration). The PIs related to 9.2 Patient's non compliance, 2.0 Untreated indication and 3.2 Length of the treatment too short were infrequent (less than 1%). The most common type of intervention was the dose adjustment. Almost 45% of these PIs involved Zopiclone or Zolpidem prescription in elderly patients. Seven hundred and nine drug interactions were identified by pharmacists. The most common type of drug interaction considered the risk of cardiac arrhythmias due to antipsychotic medications. One hundred and thirty-three PIs concerned adverse drug reaction. The most frequent adverse drug reactions were a fall (36 PIs), hemorrhage/bleeding (32 PIs), drowsiness (12 PIs) and extrapyramidal syndrome (12 PIs). Antidepressant drugs were the greatest pharmacological class concerning adverse drug reaction. The overall acceptance rate was 57%. Eight hundred and seventy-four PIs (19%) were refused and 1111 (24%) were non-assessable. DISCUSSION: PIs avoids drug-related problems, such as the polyprescription of benzodiazepine or supratherapeutic dose. However, few PIs concern compliance to therapy or polyprescription of antipsychotic drugs. These two categories of medication-related problems are known to be an issue in mental health therapy. The lack of guidelines describing mental health pathology (such as the HAS guideline) is an obstacle for performing evidence-based PIs. The lack of information describing the context of the prescription is a limitation of this study. In order to improve their practice, pharmacists have to focus more on the context in which patients are evolving, and to take into account its entire situation based on Anglo-Saxon approaches. A second way is to identify clinical settings where PIs are useful and to describe PIs needed. Doctors and pharmacists should get together and talk about these clinical situations and PIs, because some may be misunderstood or disapproved by prescribers. This collaboration could take the form of a thesaurus combining clinical situation and PIs. CONCLUSION: It appears important for pharmacists to show their daily involvement in the quality of medical care. This feedback on medication problems encountered and PIs proposed should help prescribers to identify clinical situations at risk. Nevertheless, this study also suggests that progress is possible. Dialogue must allow pharmacists and physicians to delete misunderstandings about their practices.

Note: Mechanical etching of atomic force microscope tip and microsphere attachment for thermal radiation scattering enhancement.

This Note describes a mechanical etching technique which can be used to prepare silicon tips used in atomic force microscopy apparatus. For such devices, dedicated tips with specific shapes are now commonly used to probe surfaces. Yet, the control of the tip morphology where characteristic scales are lower than 1 µm remains a real challenge. Here, we detail a controlled etching process of AFM probes apex allowing micrometer-sized sphere attachment. The technique used and influent parameters are discussed and SEM images of the achieved tips are given. Deceptive problems and drawbacks that might occur during the process are also covered.

Habituation to treadmill walking.

The use of a treadmill to evaluate gait patterns makes it possible to analyze many gait cycles and stride to stride variations. The objective of this study was to assess the time required for a subject to habituate to walking on a treadmill. The evolution of knee kinematics and spatio-temporal parameters were analyzed to measure habituation to walking on the treadmill. To obtain this information, data were recorded on 10 healthy subjects for about 45 minutes as they walked on a treadmill. A steady state was attained for knee kinematics and most spatio-temporal parameters at the time the treadmill had attained its maximal speed (approximately 30 seconds). However, 10 minutes were necessary for stride length to become reproducible. Time for habituation to walking on a treadmill must be considered when kinematics are evaluated during gait of healthy and disabled subjects. We have shown that, at least for young, healthy individuals who are non-naïve to walking on a treadmill, a 10-minute warm-up is enough before three-dimensional knee kinematics and spatio-temporal data can be recorded.

Estimation of tibial and femoral 3D linear accelerations during gait.

Shock wave traveling through the skeletal are more and more considered in the development of articular disorders. A method to quantify those skeletal transients is to estimate body segment linear accelerations. However, linear accelerations magnitude is influenced by many factors such as location and fixation of sensors, walking velocity, walking level and also by wearing conditions. Hence, experimental results in literature can't be easily compared and normative data haven't been established yet. The present paper proposes a method to estimate three-dimensional (3D) tibial and femoral linear accelerations during treadmill walking. 15 able-bodied subjects were evaluated. 3D kinematics data recorded from an optoelectronic system (Optotrak 3010, Northern Digital, Canada) at knee joint level were derived to estimated 3D linear accelerations of the tibia and the femur at their respective coordinate system origins.

[Parasitological profile of urinary schistosomiasis of the Sourou hydroagricultural complex of Burkina Faso]. / Profil parasitologique de la schistosomose urinaire du complexe hydroagricole du Sourou au Burkina Faso.

In the Sourou area of Burkina Faso, parasitological and malacological surveys of urinary schistosomiasis have been carried out in the constructed sites of Guédougou, Niasan and Débé dating respectively from 1967, 1986 and 1996. The investigations covered also the traditional villages of Lanfiera, Di, Poro, Tiao and Mara situated in the middle of the hydroagricultural planning for the first, very close to the lake for the second and about twenty kilometres distant for the three last. These towns represent the main sites in the Sourou area. The results of the parasitological surveys showed that urinary schistosomiasis was present in all sites. The levels of prevalence varied considerably: 70.3% in Guiédougou, 40.8% in Niassan, 8.5% in Débè in the irrigated zone, 55.6% in Lanfiéra, 56.8% in Di, 13.2% in Poro, 83.3% in Tiao and 64.7% in Mara. Concerning the malacological investigation, two species (Bulinus senegalensis and B. truncatus) were shown to be intermediate hosts of Schistosoma haematobium. The first was endemic to the area while the second was compatible with S. haematobium from the Sourou and other zones. Compared to the results of earlier investigations, the endemic had worsened with differences according to sites. This disparity of prevalence levels which has already been observed in other hydroagricultural area results from many factors, among which the impact of irrigation activities, the aquatic biotope system (irrigation canals, natural lake, pools and temporary rivers) and the type of contact of human communities with water rank high. Schistosomiasis expansion is amplified by the intermediate host dynamics and the introduction of new schistosomes carried by the new workers arriving from all over the country. In these conditions, in order to reduce rapidly prevalence levels, preventive measures should be centred on chemotherapy for the population. The treatment should be administered during a period of weak intermediate host density and be directed towards in-coming workers. Such an approach should be able to check the spread of schistosomiasis naturally occurring with the irrigation of new sites.

Theoretical study of transient phenomena in near-field optics.

A time-domain study of the propagation of a light pulse is made by the finite-difference time-domain method. This method is described briefly and then two applications are presented: creation and diffraction of surface plasmons in the time-domain, and propagation of a light pulse through two tip models, a dielectric one and a metal-coated one. Results on propagation speed of surface plasmons, spatio-temporal shape and spectral study of the field emitted by a tip are presented.

Shaping the reflection near-field optical probe: finite domain time difference modelling and fabrication using a focused ion beam.

An optical fibre ending in a trihedral tip is proposed as a convenient probe for reflection near-field optical microscopy in emission/collection mode. Its shape is obtained by ion milling. A first example of manufacturing and numerical models using the bi-dimensional FDTD method is presented. It confirms the strong influence of the facet angle on the intensity reflected by the probe, which is predicted by a rough analysis. This method can help us to optimize the 'reflection probe' by reducing this offset signal.

["CLAPSEN", a global approach to the rehabilitation of severe childhood malnutrition in Bolivia]. / Le <>, une démarche globale pour la réhabilitation nutritionnelle de l'enfant gravement mal nourri en Bolivie.

The "CLAPSEN" approach was developed at the Hospital Materno Infantil German Urquidi in Cochabamba, to provide a global response for the study and treatment of childhood malnutrition. "CLAPSEN" is short for Clinical, Laboratory, Anthropometry, Psychology, Sociology, Nursing (Enfermera in Spanish) and Nutritional care. Most of the malnourished children admitted to Cochabamba Hospital are from poor families, more than three quarters of whom have only recently arrived in the city. Acute malnutrition is just one of the manifestations of a generally unfavorable environment. Malnutrition should not be considered as a simple deficiency in energy, protein or micronutrients, but rather as a multi-deficiency syndrome, also involving a lack of basic health and social care. This study demonstrates that malnourished children display a considerable degree of psychological retardation and of immune system depression. After five weeks of rehabilitation, the children were considered to have recuperated physically, as assessed by anthropometry, but not psychologically, as assessed by the adapted Dewer Score, or immunologically, as shown by the size of the thymus or the extent of maturation of lymphocytes. This strategy was not designed as a long-term approach for treating malnutrition, but rather as a research project to characterize the children arriving at the hospital, to determine the reasons for their malnutrition and to identify strategies that could be implemented earlier by health centers of social services, to prevent deterioration in the condition of these children to severe malnutrition requiring hospital admission. We believe that, in this Latin American context, in which the rate of acute malnutrition is low, the hospital should continue to be involved in the treatment of severely malnourished children with associated diseases. The child's stay in hospital should be short and once the child has recovered clinically, he should be sent home. In light of the observed levels of social deprivation, psychosocial and immune deficits, there appears to be a need for continued support for the family, to ensure the full recovery of the child and to prevent relapses.

[Schistosomiasis in the region of Ziga (Burkina Faso) before the construction of a dam]. / Les schistosomoses dans la région de Ziga (Burkina Faso) avant la construction du barrage.

The authors report the results of a survey on schistosomiasis in the zone of Ziga (Burkina Faso) where a dam is going to be built. They examined 438 children aged from 7 to 15 years in 5 villages. The appraisal of macroscopic or microscopic hematuria, urine filtration, stool analysis and ultrasonographic examination made possible the assessment of the prevalence and severity of both schistosomiasis. The area was hyperendemic for urinary schistosomiasis. The general prevalence of S. haematobium was higher than 46% and 55% of the children presented at least one lesion of the bladder and 2% of hydronephrosis at ultrasonography. Intestinal schistosomiasis was not observed although few cases have been described in the regional hospital and intermediate host snails have been collected in the area. A surveillance of schistosomiasis, based on school surveys, was strongly recommended in the dam area.

Spectroscopic study of the image formation in near-field microscopy, near an evanescent-homogeneous switching.

Near-field optical microscopes provide highly resolved images of various samples. However, images are difficult to interpret owing to their sensitivity to illumination conditions. Moreover, by contrast with classical microscopy, the near-field signal combines the contributions of evanescent and propagative modes. In this study, we present results of a spectroscopic study in near-field. Our purpose is to explain how a switching of one diffracted mode from homogeneous to evanescent can modify image formation. The main point is to establish a relation between the evanescence of one diffracted mode and the fringes that are often observed in near-field experimental images. Moreover, on a metallic sample, the possible occurrence of plasmon resonance contributes to image distortion in a mainly different way. We use a Fourier series Rayleigh 3D method to explain image formation.

Surface imaging in near-field optical microscopy by using the fluorescence decay rate: a theoretical study.

In this paper, we study the fluorescence decay rate of a molecule above a corrugated interface, and particularly the variations of the decay rate as a function of the lateral position of the molecule. As a first step, one has to determine the field diffracted by a corrugated interface when the incident field is the field emitted by a dipole. For this purpose, we have used a perturbative Rayleigh method, and we show that the decay rate variations can be connected to the surface profile via a transfer function. Some numerical calculations of this transfer function and of decay rate variation images are presented for dielectric and metallic samples. The visibility of the theoretical images is up to 20% and, moreover, resolution of the images is good enough to use the fluorescence lifetime of molecules as signal in a life-time scanning near-field optical microscope. The technical problems are discussed briefly.

Immune recovery of malnourished children takes longer than nutritional recovery: implications for treatment and discharge.

Protein-energy malnutrition decreases cellular immunity yet immune recovery has rarely been investigated during nutritional rehabilitation. Malnourished children from low income families of Cochabamba (Bolivia) were hospitalized for 2 months in the Center for Immune and Nutritional Rehabilitation (CRIN), of the German Urquidi Materno-Infantil Hospital. They received a special four-step diet. Nutritional status was determined by a daily clinical examination and weekly anthropometric measurements. Immune status was assessed by weekly ultrasonography of the thymus. The classical criterion for discharge (90 per cent of median reference weight for height) was reached after the first month, whereas a 2-month period was required for complete immunologic recovery. The children belonged to disadvantaged population groups with high exposure to disease. In such an environment, discharge based only on nutritional status after 1 month of treatment could explain frequent relapses because the children were still immunodepressed.

[Large dams, health and nutrition in Africa: beyond the controversy]. / Grands barrages, santé et nutrition en Afrique: au-delà de la polémique.

The population in sub-Saharan Africa is growing faster than increases in food production, resulting in a net decrease in food production per capita. The Food and Agriculture Organization has stated that there is a "risk of widespread hunger" which could be prevented by "effective planning of water resources". However, the potential effects of such schemes on the human population are often inadequately assessed and the effect of large dams on human health is not clear. The potential risk to human health of water resources was emphasized a few years ago but no effective preventive programs were implemented, probably because of inadequate availability of information and lack of awareness. The effects on health of "large" water resource projects are not uniform within a population. Decision-makers have tended to focus on the positive effects, to obtain support for their plans. These include: 1) improvement in the well-being of the population (safe water more readily available, new infrastructure, better access to health care) and 2) increases in the food supply (more vegetables and fish available due to irrigation). Thus, there has been a logical expectation that more, better quality food will become available as a result of these schemes, whereas in fact, health and nutrition has often worsened, particularly in young children. Most of the diseases associated with water resource management are communicable, including diseases directly related to the presence of large quantities of water, such as: malaria, which increases in incidence immediately after the building of the dam, after which a new balance develops between the human population and the parasites, schistosomiasis, the disease which increases most in response to the building of dams, particularly in its most severe gastrointestinal form, diarrhea, as water is a major means of dissemination for many organisms, including those causing digestive tract infections and gastroenteritis (amebiasis, salmonellosis, cholera), due to poor sanitation, other parasitic infections, such as onchocerciasis and trypanosomiasis, which should be monitored as they may also threaten the population. Other communicable diseases may appear or increase in incidence with the influx of migrants to the irrigated area. Sexually-transmitted diseases and HIV infection are a particular problem. The large numbers of insects (mosquitoes, blackflies) may also have harmful effects on populations adapting to the new environment. These effects are related to each other and to the environmental changes. New types of food affect people's feeding habits and generate new sources of income. However, they may also lead to new and higher expenditure. There are also likely to be major socio-demographic changes associated with changes in reproductive behavior and women's activities. The location and nature of new homes and infrastructure (e.g. schools, health centers, roads) also contribute to the success or failure of the dam project. There are many constraints to be considered and a more comprehensive approach to the problem is required. Health and nutritional status may be used as simple indicators of the ability of the population to adapt to a new environment. This makes it possible to construct a causal model to identify the most effective and relevant areas of intervention. Health and nutrition issues are of vital importance and scientific findings should be used in decision-making processes for planning future large dam schemes.

Quantitative comparison of casein and rapeseed proteolysis by pancreatin.

The problem of quantitative comparison of kinetic curves was solved for casein and rapeseed pancreatin hydrolysis in a membrane reactor, which ensured the measurement of proteolysis kinetics for the products with a molecular weight of less than 1000. Coordinates were derived which provided good linearization of kinetic curves and the determination of relative rate constants irrespective of reagent concentrations, E0/S0 ratio and time intervals of kinetic measurements. When the relative rate constants of the release of the individual amino acid residues in the low-weight proteolysis products were compared, trypsin-dependent constants (for Lys and Arg residues) were found to be two times less for rapeseed than for casein, and chymotrypsin-dependent constants (for Tyr and Phe residues) were approximately 1.3 times higher for rapeseed than for casein. Statistical analysis demonstrated that the distribution of constants was narrower for rapeseed than for casein. Differences between target (Arg, Lys, Tyr and Phe) and non-target constants of release in the form of peptides and free amino acids, or in the form of free amino acids only, were attributed on the differences in the peptide bond masking for casein and rapeseed proteins. Computer simulation of proteolysis kinetics was performed by PROTEOLYSIS program package to confirm the dependence of rate constant distribution on the state of masking.

[Immuno-nutritional recovery of children with severe malnutrition]. / Réhabilitation immunonutritionnelle d'enfants atteints de malnutrition sévère.

In developing countries, more than 12 million children die each year from the combined effects of malnutrition and infection. Malnourished children have impaired cellular immunity and are particularly sensitive to opportunistic infections. However, immune recovery has rarely been investigated during nutritional rehabilitation. Indeed, mortality remains high during renutrition, and relapses are frequent. We established a center in Cochabamba, Bolivia, specifically to save these children by treating both clinical and nutritional problems and restoring immune function. The CRIN (center for immuno-nutritional recovery) admits children with severe malnutrition from the Cochabamba suburban area. They are from low income families, in crowded living conditions with poor sanitation and are weaned early. Nutritional diagnosis was based on weight-for-height, arm to head circumference ratio and clinical examination for edema, loss of subcutaneous tissue and diminished muscle mass. The children were examined daily, and first treated for respiratory and intestinal infections. Sociological and psychological aspects were also included in our holistic approach to treating severe malnutrition. Children received a four-stage diet lasting 2 months. During the initial phase (1 week) they were given an oil-sugar-milk based diet, with half lactose concentration, seven times a day. This supplied 1.5 to 2.5 g of protein and 120 to 150 kcal/kg of body weight, according to the PEM pattern. Protein and energy intake was then slowly increased during the transition phase (1 week). During the next, 'calorific-protein bombing' phase (6 weeks) 5 g of protein and 200 kcal/kg of body weight were given daily, such that there was sufficient energy for protein accumulation. During the last, discharge phase (1 week), the protein and energy contents were slowly decreased. Weight, height, arm and head circumferences, and triceps skin-fold thickness were measured weekly by standardized methods. Thymus size was assessed weekly by mediastinal ultrasound scanning with a portable scanner (ALOKA SSD-210 DXII, Tokyo) using a 5 MHz linear pediatric probe. Lymphocyte subpopulations in peripheral blood were investigated monthly using monoclonal antibodies. Compared to controls, the malnourished group had severe involution of the thymus, a significantly higher proportion of circulating immature T lymphocytes and a lower proportion of mature T lymphocytes. The two month longitudinal study showed that normal anthropometric values (90% NCHS weight for height) were recovered after one month of rehabilitation. However, immune recovery (thymic area of 350 nm2) required two months. This may explain the frequent relapses among malnourished children discharged after one month on the basis of 'apparent nutritional health'. Such children may remain immunodepressed, and should therefore be considered as high risk children. To test an immunostimulatory treatment, we designed a historical cohort study of malnourished children who received 2 mg of zinc per day. The children were matched for age, sex, anthropometric criteria and nutritional status with malnourished control children (treated previously with zinc). Anthropometric recovery was obtained in both groups in one month. Children receiving zinc attained immunological recovery within one month, whereas children not receiving zinc took two months. Thus zinc hastened immunological recovery concomitant with nutritional recovery such that the duration of hospitalization could be halved: after one month of this immuno-nutritional treatment, malnourished children appear to be sufficiently healthy to face their pathogenic home environment.

[Training needs for educators and nurses using the individualized services plan in mental health]. / Les besions de formation des éducateurs et infirmières utilisant le plan de services individualisé.

With the help of the method elaborated by Herskowitz (1977), this study examines the training needs of 42 workers (19 educators and 23 nurses) using when needed, the individualized services plan in a context of external services (deinstitutionalization) in mental health and internal services (hospital). A modified version of a questionnaire developed by Hurteau (1988) adapted to the context of mental health, identifies the training needs of workers using the individualized services plan under five specific dimensions and three types of knowledge. In the light of results obtained, certain training needs appear as top priority, especially conducting meetings and methods of elaboration of individualized services plan. Moreover, workers would like to obtain training on community-oriented services offered to people with needs in mental health.

In vitro lymphocyte-differentiating effects of thymulin (Zn-FTS) on lymphocyte subpopulations of severely malnourished children.

This work investigates how thymic dysfunction contributes to the depression of cell-mediated immunity in protein-energy malnutrition (PEM). In Bolivian children hospitalized for severe PEM, the size of the thymus was measured by echography, and the lymphocyte subpopulations were detected by using monoclonal antibodies. These data were compared with those obtained from healthy control subjects. Regardless of the clinical form of PEM, our results show a high degree of T lymphocyte immaturity in severely malnourished children, which correlates with a severe involution of the thymus. Before in vitro incubation with thymulin, this significant increase in the percentage of circulating immature T lymphocytes was concomitant with a decrease in mature T lymphocytes and a slight increase in cytotoxic T subpopulations. After in vitro incubation with thymulin, immature T lymphocytes decreased and mature T lymphocytes increased.

Metabolic and contractile responses of rat fast-twitch muscle to 10-Hz stimulation.

Contractile and metabolic responses of rat fast-twitch gastrocnemius-plantaris muscles were studied. Acute in situ 10-Hz stimulation (STIM) for two 60-min periods, separated by 60 min of recovery (REC), was used. Muscles were removed at 1, 3, 15, 60, 75, 120, 123, or 180 min for metabolite measurements. Twitch and tetanic tensions were reduced to 36 and 28% of initial during the first 60 min of STIM. During REC, these tensions returned only to 56-58% of initial by 120 min. These contractile responses did not parallel changes in metabolites in mixed muscle. pH was reduced from 7.0 to 6.4 by 1 min, but by 15 min of STIM had returned to resting levels. Free ADP and AMP increased 3- and 15-fold during STIM, then decreased to resting levels by 3 min of REC. The most sensitive indicator of metabolic stress during STIM and REC was the phosphorylation potential, which varied up to 40-fold. After initial phases of depletion, ATP and phosphocreatine levels were partially restored despite ongoing STIM. Approximately 75% of the change in ATP level could be accounted for by IMP. In red gastrocnemius [fast-twitch red (FTR)] muscle, IMP was increased by 3 min of STIM but returned to control values by 60 min. Thus reamination of IMP occurred during contractions of FTR muscle. Metabolic and contractile responses during the second STIM period (120-180 min) were similar to the first. This cycle of metabolic and contractile responses occurs in fast-twitch muscle which, with chronically repeated STIM and REC periods, undergoes large phenotypic changes as a result of use.