Management Of Asthmatic Patients Research Articles

The Relationship between Exhaled Nitric Oxide Measured with an Off-line Method and Airway Reversible Obstruction in Japanese Adults with Asthma

Exhaled nitric oxide (eNO) is a useful marker of eosinophilic airway inflammation in asthma patients. There is no study to show the relationship between the eNO measured by using an off-line method and the degree of reversibility of airflow limitation in Japanese asthma patients. We sought to investigate the relationship between the eNO level measured by using an off-line method and the degree of reversibility of bronchial constriction in Japanese asthma patients. The study population comprised 97 asthma patients in our outpatient clinic with some patients in both groups who received inhaled corticosteroid treatment. We measured eNO levels, forced expiratory volume in one second (FEV1) before and after treatment, reversible airway obstruction (DeltaFEV1) after inhalation of bronchodilator, and other parameters. eNO was significantly correlated with peripheral blood eosinophil counts in asthma patients (in steroid-naïve asthma patients, r=0.544, p<0.0001; in asthma patients treated with inhaled corticosteroid, r=0.463, p=0.026), and subjects with severe eosinophilia in sputum showed high levels of eNO (mild eosinophilia versus severe, p=0.0152). Among patients with obstructive impairment, eNO levels were correlated with DeltaFEV1 regardless of whether patients received (r=0.527, p=0.0435) or did not receive (r=0.64, p = 0.0056) inhaled corticosteroid. In subjects with normal pulmonary function, there was no significant relationship between eNO and DeltaFEV1 with or without inhaled corticosteroid. In patients with obstructive impairment, eNO reflects the degree of reversible airflow limitation. In subjects with normal pulmonary function, eNO may facilitate the diagnosis and management of asthma, rather than indicate reversible bronchial obstruction. eNO measurement by off-line methods is applicable as a potential tool for the diagnosis of asthma and management of asthma patients.

Management of asthma in patients supervised by primary care physicians or by specialists

French asthma patients may be supervised by general practitioners (GPs) and/or specialists. Therefore, this study examined asthma management in patients exclusively supervised by specialists (SPE), GPs, (GP) and both (GP+SPE group), and compared the findings. Asthma patients were consecutively recruited in 348 pharmacies. Each patient completed a questionnaire providing data on personal characteristics, asthma management, perception of disease and asthma supervision. Asthma control was measured using the Asthma Control Test. Questionnaires were linked to computerised records of medications which had been dispensed before inclusion in the study. From the 1,256 patients (mean age = 36.1 yrs, 54.3% females), 11.4, 36.6, and 52.0% were placed in the SPE, GP, and GP+SPE groups, respectively. During the previous 4 weeks, most patients in the SPE group were properly controlled (52.2 versus 26.4 and 21.5% in GP and GP+SPE groups, respectively). The SPE group made more use of fixed combinations of long-acting beta agonist and inhaled corticosteroid, while receiving less short-acting beta agonists, antitussives and antibiotics. Striking differences in symptoms and asthma management were observed according to the type of asthma supervision. The current results strongly support the need to improve the management of asthma in primary care, and the coordination of care between general practitioners and specialists.

Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid‐intolerant asthma

The thromboxane A2 receptor (TBXA2R) is a receptor for a potent bronchoconstrictor, TBXA2 which is known to be related to bronchial asthma and myocardial infarction. TBXA2R antagonist and TBX synthase inhibitors have been found to be effective in the management of asthmatic patients. This study was aimed to evaluate whether genetic variants of TBXA2R may be related with development of acetyl salicylic acid (ASA)-intolerant asthma (AIA). TBXA2R gene polymorphisms (TBXA2R+795T>C, TBXA2R+924T>C) were determined using a single-base extension method in 93 AIA patients compared with 172 patients with ASA-tolerant asthma (ATA) and 118 normal controls (NCs) recruited from the Korean population. HLA DPB1*0301 genotype was performed using a direct sequencing method. The rare C allele frequency of TBXA2R+795T>C was significantly higher in AIA than in ATA (P=0.03) and the TBXA2R+795T>C polymorphism was also associated with extent of percent fall in forced expiratory volume in 1 s (FEV1) after the inhalation of lysine-acetyl salicylic acid in AIA patients (P=0.009); AIA patients homozygous for the +795 C allele had a greater percent fall of FEV1 compared with individuals with TBXA2R+795 CT or TT genotypes. The frequency of patients carrying both the TBXA2R+795T>C rare allele and HLA DPB1(*)0301 was significantly higher in AIA patients (29.4%) than in ATA patients (7.3%) (P=0.008, odds ratio=5.3). These results suggest that the polymorphism of TBXA2R+795T>C may increase bronchoconstrictive response to ASA, which could contribute to the development of the AIA phenotype.

Efficacy of management programme for asthma patients in military servicemen with regards to international guidelines

Management of asthma patients is little known in departmental, partly in military medicine. This study was designed to evaluate the efficacy of a management programme for asthmatic militaries. We assessed asthma attack rate (day and nighttime), need in bronchodilators, peak expiratory flow rate and forced expiratory volume for 1 s as per cent of predictive values, number of acute exacerbations and admissions to a hospital per a year and their length, days lost from work, calls for emergency aid before and 1 year after implementation of the programme. We found significant reductions in frequency of nighttime asthma attacks, need in bronchodilators, number of calls for emergency aid, rates of acute exacerbations and hospitalizations, their length, improvement in lung function. Therefore, we concluded that the management programme for asthmatic militaries is effective.

The role of measuring airway hyperresponsiveness and inflammatory biomarkers in asthma

Asthma is characterized by inflammation and airway hyperresponsiveness, which results in episodic airflow obstruction. It is diagnosed once a compatible clinical history plus objective evidence of diurnal variability in peak expiratory flow or significant reversibility to inhaled bronchodilator is documented. In accordance with current guidelines, measures of airway calibre and symptoms allow patients and clinicians to assess the degree of asthma control and titrate pharmacotherapy. However, these parameters fail to reflect the extent of underlying endobronchial inflammation and airway hyperresponsiveness, which in turn suggests that additional measures of asthma control may be of benefit. This evidence-based review highlights ways by which inflammation and airway hyperresponsiveness can be assessed and how they may provide additional useful information in the diagnosis and management of asthmatic patients.

Improving asthma symptom control in rural communities: the design of the Better Respiratory Education and Asthma Treatment in Hinton and Edson study

Methods The prevalence of asthma in adults in the United States is approximately 7%, and 9% of asthma patients will require hospitalization each year. Many patients do not seek care, as they do not recognize overuse of beta-agonists as a risk factor for poorly controlled asthma. However, pharmacists are able to identify these patients through refill information on reliever medication prescriptions and potentially initiate community-management opportunities for these patients. Design The study is a randomized, controlled trial. Patients are randomized to intervention or usual care. Study population Patients are high-risk asthma patients (defined as having an ER visit or hospitalization in the previous year, or using >2 canisters of short-acting beta-agonist in the previous 6 months). They are identified through community pharmacies. Objectives The primary objective is to determine the effect of an education and referral intervention program initiated by community pharmacists, working with high-risk asthma patients, family physicians and respiratory therapists, on asthma control, as measured by the Asthma Control Questionnaire (ACQ). Secondary objectives include determining the effect of this program on ER visits/hospitalizations, inhaled corticosteroid use, courses of oral steroids and FEV 1. Intervention The intervention includes patient education, assessment and optimization of drug therapy, and physician referral as needed. Patients are referred to a respiratory therapist within 1 week of randomization for measurement of FEV 1 and reinforcement of education. Patients assigned to usual care receive written asthma information, referral to a respiratory therapist and usual pharmacy and physician care. Unique aspects The design of the Better Respiratory Education and Asthma Treatment in Hinton and Edson (BREATHE) study is unique, given the multidisciplinary involvement, rural and community based, pharmacist initiated and targets specifically high risk patients. We believe that this study will show that management of asthma patients, involving the major role-players in their asthma care, will improve their asthma control.

The impact of budesonide and other inhaled corticosteroid therapies in the management of asthma in children and adults

Background: Since the recognition that asthma is characterized by extensive inflammation of the airways, the use of inhaled corticosteroids (ICSs) as controller therapy has become central to successful disease management. As the prevalence of asthma increases worldwide, there is concern about increasing numbers of patients with untreated or undertreated asthma, which may lead to deterioration in disease control, with direct effects on morbidity and mortality rates. The costs attributed to asthma translate into a considerable economic burden, from the direct costs of medical treatment to the costs incurred through lost work or school days. International treatment guidelines currently recommend early intervention with ICS therapy to improve lung function and disease control. Objective: This article reviews the role of therapy with ICSs, particularly budesonide, in improving the management of asthma in patients of all ages and in reducing the economic and social burdens of this disease. Results: Randomized, controlled clinical studies confirm the efficacy of early intervention with ICSs in patients with mild persistent asthma. Regular use of an ICS can reduce the number of exacerbations and hospitalizations in patients of all ages and with all disease severities. Conclusions: Budesonide has a well-established efficacy and safety profile. Its once-daily dosing may contribute to improved adherence and cost-effectiveness.

Written self-management plans improve asthma control.

Health Sciences Centre, University of Calgary, Calgary, Alberta Correspondence and reprints: Dr RL Cowie, Health Sciences Centre, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1. Telephone 403-220-8981, fax 403-270-8928, e-mail Cowie@ucalgary.ca Patient participation is necessary for the treatment of any chronic disease but particularly for diseases that run a variable course. The day-to-day variability of asthma demands careful participation by the individual with the disease and his or her caregivers if they are to achieve optimal control and enjoy a normal lifestyle (1). Most, if not all, asthma guidelines emphasize that patient education is as important as the prescription of appropriate medication (1). Indeed, the prescription and the education are inseparable. Without instruction in the use of inhaler devices, without the knowledge of what constitutes disease control, and without the understanding of the role of medical and nonmedical interventions, it is not likely that asthma control will be achieved, even when all of the relevant medications have been prescribed. Patient education in a variable disease must also include some component of disease monitoring linked with a self-management plan. Probably the most important aspect of patient education toward self-management is preventing the development of severe and potentially life-threatening exacerbations (2). Unfortunately, it has been shown that even those patients who have a good knowledge of their disease may not apply this knowledge to the management of an exacerbation of their asthma (3). The appropriate use of self-management plans in asthma thus requires careful education with the emphasis on changing behaviour (rather than the acquisition of knowledge). Action plans are not suitable for all patients with asthma (4) and are most effective in those with more severe disease (5). It is often difficult to provide an evidence base for an intervention, such as asthma self-management, that requires people to change their behaviour. This difficulty is demonstrated by the conflicting conclusions of two recent Cochrane reviews of this topic (6,7). The former review concluded that the inclusion of a written action plan in an education program for asthma improved health outcomes (6). The latter review of an almost identical selection of studies concluded that only six published studies were valid and that there was insufficient evidence to support the value of action plans (7). In fact, only one of the cited studies examined the impact of an action plan versus no action plan (8); the other five studies compared different types of plans, or an education program and an action plan with no education or plan (7). Even one of the most recent studies failed to examine self-management plans on an even playing field, although it did suggest, as may be expected, that a plan without appropriate education is unlikely to result in a change in behaviour (9). The lack of evidence to support the role of action plans in patient management of asthma should not be seen as evidence of lack of efficacy. We know that it is very difficult to change behaviour, but that difficulty should not stop us from instructing our patients to manage their asthma any more than it should stop us from offering advice on smoking cessation or other difficult interventions that require behavioural change. Notwithstanding the admittedly incomplete evidence, it is difficult to avoid the conclusion that written action plans should be part of the management of asthma in patients, especially in those who suffer from severe exacerbations (5,8) and who are ready to make behavioural changes (10,11).

Review of the role of Magnesium Sulphate in the Management of Asthma patient at A&amp;E Setting

Controversial views exist with regards to the use of intravenous magnesium sulphate in patient with severe asthmatic attack. The benefit of intravenous magnesium sulphate may be masked by the pooling of patients with different pathophysiology. The subsets of patients with severe asthmatic attack who have not responded to nebulised bronchodilator therapy and intravenous steroid therapy may benefit from intravenous magnesium sulphate therapy.

Concernment of Drug Consultation on Improvement in Patient's Knowledge by Pharmacist.

The purpose of the report is to assess the effectiveness of drug consultations by pharmacists in accordance with a prospective controlled study for asthma patents during a four month period. This prospective study was based on a questionnaire and interview for asthma patients to investigate the disease recognition. The subjects consisted of 43 male and female asthma patients who were treated with theophylline and other drugs between September 1997 and December 1997. In particular, the subjects receiving drug consultations consisted of 17 patients, who were all outpatients with asthma disease. The severity and incidence of asthma symptoms and the knowledge of prescribed drugs for patients were obtained by the questionnaires. In addition, we directly interviewed 32 male and female patients, who replied to the questionnaire, to evaluate his/her understanding of drug therapy with asthma. We then determined the values. The values were expressed as the means ± S.D. of nobservations for each score. In this study, the average age of the subjects was 56.5 years. The drugs used for the asthma patients were inhaled steroids, theophylline, expectants, inhaled bronchodilators and anti-allergic agents (such as thromboxane A2 synthesis inhibitors, leukotriene receptor antagonists). The number of correct answers for inhaled anti-inflammatory agents and inhaled bronchodilator agents were significantly better than those of the non-consultation patients during our observation period. In addition, in the stepwise approach for asthma patients treatment, the peak flow monitoring usage and recognition both improved by pharmacist's drug consultations with asthma patient. In this study, we indicated that the drug consultations by pharmacists exercises have a favorable effect on the management of asthma patients.

Can Peak Expiratory Flow Measurements Estimate Small Airway Function in Asthmatic Children?

Asthma is characterized in part by small airways dysfunction. Peak expiratory flow (PEF) measurement has been suggested by all international guidelines as an important tool in asthma management. The correlation between PEF and FEV(1) but not with forced expired flow at 50% of vital capacity (FEF(50)) is well-established. To determine the value of PEF measurement as a predictor of small airways status as expressed by FEF(50). Analysis of the association between PEF and FEF(50) in single and multiple determinations. One hundred eleven asthmatic children (mean age, 11.8 years), grouped in the following way according to FEV(1) values: within normal range (n = 46); mildly reduced FEV(1) (n = 44); and moderately/severely reduced FEV(1) (n = 21). Overall, FEF(50) and PEF were significantly correlated (r = 0.49; p < 0.0001). However, in 41.6% of the patients, the actual FEF(50) differed by > 20% from the calculated FEF(50). PEF has a high specificity (82.4%) but a poor sensitivity (51.7%) to detect FEF(50) status. PEF was better able to reflect abnormal FEF(50) in the patients with more severe asthma and to reflect normal FEF(50) values in the healthier patients. In patients with multiple measurements (n = 40), the correlation between FEF(50) and PEF was significantly better than that derived from a single determination (multiple measurements r = 0.77; single measurement, r = 0.49). Although PEF is an important tool in the management of asthmatic patients, it does not yield a complete picture because it is not sensitive in detecting small airways function. It is best used at home along with regular spirometry measurements at the clinic. PEF may serve as a better index of changes in small airways function once an individual regression is determined.

Asthma: best treatment options

To understand the principles of asthma management in patients of different ages, and to outline major avoidance measures, classes of medications available, and indications for immunotherapy (IT). MEDLINE and major textbooks of allergy and immunology. There has been an understanding of asthma as a chronic inflammatory disease for many decades but recent information about mediators and cytokines has led to new therapies and better understanding of the effects of IT and other preventive measures. The best treatment for any individual patient depends upon many factors and is a decision to be made between the patient and the physician. It seems that the best response to IT occurs in those who are highly sensitive to unavoidable allergens, and who experienced a late-phase asthmatic response to the allergen initially. New data suggest that IT should be considered early, as it may prevent progression of asthma to more severe, less reversible disease. The best therapy results in the ablation of airway early- and late-phase reactivity.

Comparación de dos modelos de educación para pacientes asmáticos

The education programs have demonstrated to be an important point in the management of asthmatic patients. The aim of the present study was to assess if an intensive group asthma education program was able to improve a simplified and individual asthma education program, both with a self-management plan included. A prospective randomised controlled trial was conducted over 12 months and 73 moderate-severe asthmatic patients were included. Patients were randomly assigned to control or study group. Patients in control group received individual and simplified education with a self-management plan and patients in study group attended an <<asthma school>> in small groups where they received a three hours education program in three weeks.The outcome measures were: number of hospital admissions, observation unit admissions, emergency visits and unscheduled general practice consultations. Knowledge, adherence to treatment, ability with inhaler devices, airway function, environmental control measures and quality of life. They were assessed at the beginning and the end of the study. At the end of the study period the outcome of morbidity had improved in both groups but the number of observation unit admissions (p = 0.028) and unscheduled general practice consultations (p = 0.022) was substantially lower in study group. This group also demonstrated improvement in environmental control measures and better inhaler technique and knowledge (p = 0.007). In adherence, lung function or quality of life there were no differences between groups. In patients with asthma better results can be obtained with an intensive group asthma education program than with the individual and simplified program.

Indoor allergens: identification and environmental control

Summary The relationship of indoor environmental allergens to asthma, especially in genetically predisposed individuals is better and better established. Knowledge of the principal indoor allergens has so far been secondary to identification of major allergen producers — both animal and vegetable — present in domestic homes. Chemical dosages of the major allergens (mainly allergens from mites and domestic animals) being now available, quantification of the allergens we are exposed to, has become possible: the most meaningful results are reported for each of them. Strategies for indoor allergen avoidance combine three methods: elimination of reservoirs of settled dust such as bed material, carpets, furnishing; control of the sources of new allergens (living mites, household pets, occasionally plants); reduction of airborne allergens. The different procedures involved in eradicating mites and eliminating mite and animal allergens are reviewed in detail. Objective data concerning the effectiveness of environmental control measures in the management of asthmatic patients are difficult to obtain, sometimes giving contradictory results. Further clinical studies are still needed with better designs concerning the most appropriate avoidance methods and criteria of patients' selection.

ALTERNATIVE ANTI-INFLAMMATORY AND IMMUNOMODULATOR MEDICATIONS FOR ASTHMA

The National Institutes of Health (NIH) 1997 Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma 12 (EPR2) proposes a standard of care for patients with this chronic, predominantly eosinophilic, inflammatory disease: that patients with mild persistent asthma be treated with daily low-dose inhaled corticosteroids, that patients with moderate persistent asthma receive higher doses of inhaled corticosteroids, and that patients with severe persistent asthma be treated with the highest doses of inhaled corticosteroids, long-acting bronchodilators, and the lowest doses of oral corticosteroids that can achieve the therapeutic goal. The EPR2 suggests other medications as add-on therapy or as alternatives. This article reviews randomized clinical trials that address alternative medications for the management of persistent asthma in patients who require daily treatment. When available, head-to-head comparisons are discussed. Traditionally, alternative anti-inflammatory treatments for asthma are given to patients with severe disease that requires higher doses of oral corticosteroids for control of symptoms. The experience of rheumatologists treating patients with arthritis has led to the suggestion that methotrexate, gold salts, hydroxychloroquine, dapsone, and cyclosporin may be of benefit for severe steroid-dependent asthmatic patients. In contrast, for patients with mild to moderate persistent asthma, alternative medications with potential anti-inflammatory effect include cromolyn sodium, nedocromil, theophylline, and the leukotriene modifiers. Several of these agents, as well as long acting oral and inhaled bronchodilators, have also been proposed as effective means to reduce the daily dose of the inhaled corticosteroid while maintaining or improving control of asthma. Outcome parameters vary among studies. The most common objective measures include forced expiratory volume in 1 second (FEV 1 ), peak expiratory flow rate (PEFR), and measures of bronchial hyperreactivity. Dosage levels of oral corticosteroids taken for asthma, albuterol use, and level of symptom control are also reported indicators of efficacy. The adverse drug profile of each therapy needs to be considered. Most clinical studies unfortunately are short-term, and many of the potential safety concerns may appear only after several years of treatment. Study populations, even when controlled for disease severity, differ among clinical investigations and make comparative analysis difficult. Randomized clinical trials of two or more therapies provide the best comparisons. In analyzing the outcomes of alternative medications, one needs to consider the placebo effect on clinical changes. Many clinical trials have demonstrated that enrollment alone can improve lung function and symptom control. In placebo-controlled trials, a clinically significant difference, not just a statistical difference, needs to be demonstrated.

Flixotide Nebules: new for chronic severe asthma.

Allen & Hanburys recently launched Flixotide Nebules for prophylactic management of severe chronic asthma in patients requiring high-dose inhaled or oral corticosteroid therapy.

Development and Evaluation of a Pharmacist-Managed Asthma Education Clinic

This study evaluated pharmacist-provided education of asthma patients and determined whether such educational services led to decreased emergency department (ED) visits and hospital admissions. The study population consisted of 22 asthmatic patients referred to the educational clinic by their primary care providers. Patients attended a series of sessions on asthma and its treatment, in which pharmacists taught them about medications and their appropriate use and assisted them with metered-dose inhaler (MDI) and peak flow meter techniques. An asthma action (self-management) plan was developed for each patient. Clinical outcome measures were frequency of ED visits and hospital admissions 1 year pre- and post- education, a patient satisfaction survey, and evaluation of asthma management skills. Prior to education only 5 of 20 patients were using MDIs as prescribed, whereas, after education, 18 of 20 patients or 90% (p = 0.0015) used MDIs correctly. The pharmacist-educated patients had a 40% reduction in hospitalizations and a 66.6% reduction in ED visits related to asthma. These reductions in hospital admissions and ED visits represented a significant cost avoidance to our institution. Our findings show that a pharmacist-run educational program can improve disease management of asthmatic patients.

Decrease in emergency room or urgent care visits due to management of bronchial asthma inpatients and outpatients with pharmaceutical services.

To evaluate pharmaceutical care of bronchial asthma over a 1-year period and to investigate whether such care is effective. 79 male and 97 female asthma patients who were treated with theophylline and other drugs between June 1994 and September 1996 were studied. The 15 subjects received pharmaceutical care (group 1) and were all inpatient asthmatics who had been admitted to the hospital for treatment. The other patients acted as controls. In 1994, the average medication cost of asthma patients without pharmaceutical care was $199/month and $295/month when such care was provided in the outpatient clinic. The drug treatments which patients received generally included inhaled anti-inflammatory agents and theophylline, but the 161 non-pharmaceutical services patients (group 2) received fewer inhaled anti-inflammatory agents than group 1 patients. The number of visits to the emergency room and hospital admissions were significantly lower in patients after receiving pharmaceutical services than inpatients before receiving pharmaceutical services during our observation period. The serum theophylline concentrations of group 1 patients generally attained levels sufficient for favourable therapeutic effect after patients received pharmaceutical care. Pharmaceutical care offered at the hospital is effective in the management of asthma patients.

The Community Pharmacist—A Vital Link in Caring for the Asthma Patient

Pharmacists in a variety of settings are in a pivotal position to contribute to effective management of asthma patients. As part of the health care team, pharmacists can identify patients with poorly controlled asthma and educate patients on asthma medications, appropriate administration technique, and how to monitor therapy. By assisting with the management of the asthma patient, pharmacists can help optimize the care asthma patients receive, while decreasing overall health care expenditures.

Ketamine and its isomers have equipotent relaxant effects on tracheal smooth muscle contracted by tachykinins

Recent studies indicate that not only inflammatory cells but also neural mechanisms by which tachykinins such as substance P (SP) and neurokinin A (NKA) are released from vagal afferent C-fiber contribute to asthma. Although ketamine (K) has been used in the anesthetic management of asthmatic patients, the mechanism by which K relaxes the airway smooth muscle is still uncertain, and no information exists on any differential effect of K and its isomers. We determined the spasmolytic effect of racemic [R(±)]K and its isomers S(+) K and R(-) K on SP and NKA-induced contraction of tracheal smooth muscle in guinea pigs. Strips of guinea pig trachea were mounted in an organ bath filled with Tyrode's solution at 37°C bubbled with 95% O2/5% CO2. Strip tension was measured isometrically with a force displacement transducer. Strip contraction was elicited with SP 10(-6) M or NKA 5×10(-7) M.R(±), R(-), or S(+) K (4.5-18.0×10(-4)M) was cumulatively administered into the bath. The calculated ED50 values (the concentration that relaxed the contraction by 50%) of R(±), R(-) and S(+) K were 7.6±0.5, 7.8±0.6, and 7.6±0.5 (10(-4)M), respectively, when the contraction was elicited with SP, and 8.0±1.0, 8.2±1.2, and 7.9±1.3 (10(-4)M), respectively, when NKA was used. We concluded that K and its isomers have equipotent spasmolytic effects on airway smooth muscle precontracted with tachykinins.