Mobility of heavy metals in sandy soil after application of composts produced from maize straw, sewage sludge and biochar - Discussion of Moussavi et al. - JEMA-D-18-00677.

The discussion letter we received was carefully reviewed by us, authors. We would like to thank Moussavi et al. for their interest and emphasis on the originality of our studies. Every substantive discussion on study results is valuable, especially when it gives a new perspective on the results obtained. We would like to note that our manuscript lacks some of the results listed by Moussavi et al., not because of our ignorance, but because of the concept of our manuscript's structure. We would like to point out that the research methods used in the published manuscript were selected based on available literature. We also want to emphasise the very diversified scientific approach to procedures for determining the availability of trace elements in soil. This approach was also noted and clearly justified in many studies. We believe that the diversity of scientists' approach to the investigated subject is a very important and creative component of science.

Mobility of heavy metals in sandy soil after application of composts produced from maize straw, sewage sludge and biochar.

Studies on the availability of heavy metals in composted organic materials and in soil amended with these materials are of practical significance. They are used in the assessment of the purity of the soil environment and of the biological value of plants intended for human and animal consumption. Composting of organic materials has a significant effect on changes in mobile forms of heavy metals. Therefore, the aim of this study was to determine the effect of the addition of biochar and sewage sludge on (i) the contents of water soluble forms of Cu, Cd, Pb, and Zn in composts; and (ii) the contents of mobile forms of these elements in sandy soil after the addition of composts. Addition of sewage sludge and biochar to maize straw did not increase the heavy metal forms extracted with water in total content of heavy metals. The content of Cd and Cu extracted with water in composts produced from maize straw and sewage sludge, and produced from maize straw, sewage sludge and biochar was higher than the one determined in compost produced from maize straw. The content of Pb and Zn extracted with water in compost produced from maize straw, sewage sludge and biochar was lower than in compost produced from maize straw. The addition of sewage sludge and biochar to maize straw had an immobilizing effect on mobile forms of the studied elements compared to compost produced from maize straw and sewage sludge. The addition of composts to soil decreased the contents of mobile forms of Cu, Cd, and Pb extracted with 1 M NH4NO3 compared to the contents in the control soil. However, the content of Zn extracted with NH4NO3 increased in treatments with 0.5% dose of compost produced from maize straw and sewage sludge and 0.5% dose of compost produced from maize straw, sewage sludge and biochar. In none of the analyzed cases, the application of the composts produced did not exceed the acceptable content of studied elements in the soil.

Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells.

Pheochromocytoma is a rare but potentially lethal chromaffin cell tumor with currently no effective treatment. Peptide hormone receptors are frequently overexpressed on endocrine tumor cells and can be specifically targeted by various anti-tumor peptide analogs. The present study carried out on mouse pheochromocytoma cells (MPCs) and a more aggressive mouse tumor tissue-derived (MTT) cell line revealed that these cells are characterized by pronounced expression of the somatostatin receptor 2 (sst2), growth hormone-releasing hormone (GHRH) receptor and the luteinizing hormone-releasing hormone (LHRH) receptor. We further demonstrated significant anti-tumor effects mediated by cytotoxic somatostatin analogs, AN-162 and AN-238, by LHRH antagonist, Cetrorelix, by the cytotoxic LHRH analog, AN-152, and by recently developed GHRH antagonist, MIA-602, on MPC and for AN-152 and MIA-602 on MTT cells. Studies of novel anti-tumor compounds on these mouse cell lines serve as an important basis for mouse models of metastatic pheochromocytoma, which we are currently establishing.

Can the functional assessment of multiple sclerosis adapt to changing needs? A psychometric validation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis.

BACKGROUND: The Functional Assessment of Multiple Sclerosis (FAMS) is widely used in clinical trial programmes; however, it was developed before the rise in trials targeted at early stage multiple sclerosis (MS) and clinically isolated syndrome (CIS). OBJECTIVE: The aim of this study was to assess the psychometric properties of the FAMS within two clinically distinct populations, CIS and early relapsing-remitting MS (RRMS), and discern the appropriateness of the FAMS within these populations. METHODS: Secondary analysis was conducted on FAMS data from two clinical trials assessing interferon beta-1b in early RRMS and CIS. The statistical analysis assessed the scale acceptability, reliability, validity and responsiveness of the FAMS. Item response theory (IRT) was also conducted on the early RRMS sample in order to assess how well the FAMS discriminated amongst individuals with less severe MS. RESULTS: Results from both trials demonstrated an improvement in the FAMS psychometric properties with increased baseline disease severity. However, high ceiling effects were evident amongst less severe patients, and there was an overall lack of responsiveness to improvement and poor construct validity. IRT also demonstrated its lack of discrimination/sensitivity in early RRMS. CONCLUSIONS: In trials involving patients with early stage RRMS and CIS, modifications to the FAMS based on a qualitative assessment of its content validity in these populations would be required in order to potentially improve the FAMS psychometric properties and sensitivity.

Early conceptual and linguistic development of a patient and partner treatment satisfaction scale (TSS) for erectile dysfunction.

OBJECTIVE: To describe the early development of a pluri-language self-report questionnaire to assess male patients and their female partners' satisfaction with drug treatment for erectile dysfunction (ED). METHODS: This first development phase proceeded in several parts. Item generation followed literature review, hypothesized characteristics of the drug and in-depth interviews with patients and their partners. Perceptions and feelings related to ED and patients' expectations of treatment were explored. Items were generated simultaneously in 5 languages (American English, Canadian French, English, French and German). Content and face validity were empirically assessed by interviews with a few patients and partners in each country. Conceptual equivalence between languages was ascertained. RESULTS: The final content domains included satisfaction with: sexual spontaneity, quality of erection, quality of ejaculation, sexual pleasure, orgasm, confidence, reliability of treatment, side effects, convenience, overall satisfaction, conformity to treatment expectations and intent to continue use of drug. Cognitive debriefing with patients and partners found few issues with comprehension, however some words were considered problematic. The simultaneous development for the different languages allowed adaptation of the content at this stage and ensured consistency of all language versions. The final questionnaire consisted of 4 modules: unmedicated patient, medicated patient, unmedicated partner, and medicated partner modules. The questionnaire was then linguistically validated into 15 additional languages for further psychometric validation. CONCLUSIONS: The Treatment Satisfaction Scale (TSS) is a multi-facetted measure of patients' and partners' satisfaction with their sexual life relating to erectile dysfunction and intended for prospective use. Its simultaneous development for a variety of countries and languages has fostered true item equivalence across language versions. However, further work is needed to validate the TSS psychometrically, including identification of domains, test responsiveness and determination of appropriate scoring prior to its clinical use.

Mild-to-moderate uncomplicated hypertension: further analysis of a cost-effectiveness study of five drugs.

A cost-effectiveness model was designed to explore the effect of adding a new angiotensin-II inhibitor, telmisartan, to the therapeutic options for treating mild-to-moderate uncomplicated hypertension. Incorporating the cost of drugs, physician visits, and adverse-event treatments, the model concluded that availability of telmisartan on formulary may shorten the mean time and costs to control. The stability of the initial findings over a range of sensitivity analyses lends credence to the model conclusions that availability of telmisartan on formulary improves the therapeutic options of care for hypertension.

Delphi panel study of current hypertension treatment patterns.

OBJECTIVE: The purpose of this study was to assess whether, and to what extent, usual practice in the management of patients with mild to moderate hypertension differs from that recommended in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI). The results were used as input for a clinical decision analytic model to assess the cost-effectiveness of a new treatment for hypertension. METHODS: A Delphi panel survey of general practitioners and cardiologists in the United States was conducted to determine current strategies for the treatment of mild to moderate uncomplicated hypertension. The purpose of the panel survey was to reach consensus on 3 key facets of the JNC-VI guidelines and how they relate to the respondents' clinical practices: (1) the definition of mild to moderate hypertension, (2) the treatment that adult patients with uncomplicated mild to moderate hypertension should receive, and (3) the management of patient follow-up. RESULTS: Of the 20 physicians contacted for the survey, 10 responded to both rounds of the questionnaire. There was considerable variation in the responses for defining the ranges of healthy, acceptable, unacceptable, and serious blood pressure. In general, the Delphi panel respondents cited higher limits than stated in the JNC-VI guidelines. Physicians followed the guidelines approximately 60% of the time. Primary determinants of initial drug choice among the panelists were comorbid conditions and the severity of hypertension; patients' age, race, and sex were secondary determinants. Follow-up typically occurred 1 month after therapy initiation. Panelists reported titrating the dose of new therapies upward once or twice before discontinuing the drug for lack of efficacy. Once adequate blood pressure control was achieved, patient follow-up was reported to occur every 3 to 4 months. CONCLUSIONS: This Delphi panel study highlights the differences between clinical practice and the JNC-VI guidelines in the treatment of hypertension. The results were used as a basis for defining a structure for a cost-effectiveness model and provided the management practice and prescribing practice patterns required by the model.

Aspirin plus extended-release dipyridamole or clopidogrel compared with aspirin monotherapy for the prevention of recurrent ischemic stroke: a cost-effectiveness analysis.

OBJECTIVE: The goal of this health economic analysis was to asses the cost-effectiveness of a fixed combination of aspirin plus extended-release dipyridamole (ASA/ER-DP) or clopidogrel compared with ASA monotherapy for prevention of recurrent ischemic stroke. BACKGROUND: The second European Stroke Prevention Study (ASA/ESPS-2), a large-scale clinical trial, demonstrated that a new therapy--a fixed combination of ASA/ER-DP--is more effective than ASA monotherapy for the prevention of recurrent ischemic stroke. METHODS: We used data from ESPS-2 to create a health economic model that estimates the incremental cost and cost-effectiveness of ASA/ER-DP during the 2-year time frame after an ischemic stroke. The model was developed from a payor perspective. The analysis used direct cost estimates for stroke from a Medicare claims database analysis. Efficacy data were obtained from clinical trials to determine the incremental cost per stroke averted for ASA/ER-DP or clopidogrel versus ASA. Sensitivity analyses also were conducted to test the reliability and robustness of the model. RESULTS: The results of the analysis demonstrated that ASA/ER-DP was cost-effective compared with ASA monotherapy for the secondary prevention of stroke, with a cost-effectiveness ratio of $28,472. The model remained robust over a range of assumptions and cost estimates. Clopidogrel, however, was not cost-effective compared with ASA (cost per stroke averted, $161,316) in either the base-case analysis or any of the sensitivity analyses. CONCLUSION: ASA/ER-DP thus offers a cost-effective alternative to ASA monotherapy for the prevention of recurrent ischemic stroke.

Developing a managed care-pharmaceutical research partnership.

Increasingly, MCOs ask pharmaceutical companies for evidence of a new product's cost effectiveness before adding it to the formulary. This article examines a research partnership between a pharmaceutical company and 14 MCOs to assess the cost effectiveness of a new medication for osteoarthritis. The research partnership, a study protocol, and research activities are discussed.

Do practice guidelines augment drug utilisation review?

Drug utilisation review (DUR) or drug use evaluation (DUE) studies or programmes are intended to detect and/or correct inappropriate drug use. Appropriateness can be assessed at 3 levels: (i) whether any medication is warranted, or whether either no therapy or nondrug therapy is preferred (level 1); (ii) assuming drug therapy is indicated, which of several alternative drugs is the preferred choice? (level 2); and (iii) appropriateness of the drug regimen, including dosage, duration, type and frequency of monitoring, and drug interactions (level 3). The traditional approach to DUR/DUE has been to begin the appropriateness evaluation after a drug is prescribed. However, changes in healthcare organisation provide the basis for a disease-management or health-maintenance approach to DUR/DUE, and practice guidelines afford a possible source for guiding such studies. We hypothesised that the latter approach to DUR/DUE would be more likely to result in evaluation of level 1 drug-therapy issues than the traditional DUR/DUE approach. We tested this hypothesis by reviewing 56 practice guidelines involving drug therapy and also reviewed research studies published from 1992 to 1996. We found that studies that used the traditional DUR/DUE approach were most likely to examine level 3 drug-therapy issues, never addressed level 1 issues, and typically evaluated adherence to provider- or study team-developed guidelines rather than published guidelines. In contrast, the disease- or health-management approach nearly always examined level 1 issues, seldom addressed level 3 issues, and almost always evaluated adherence to a published practice guideline. Regardless of the DUR/DUE approach, about 40% of studies evaluated level 2 issues. The guidelines themselves were much more likely to include recommendations about level 1 and level 2 issues than about level 3 issues; however, even when a guideline included level 2 or level 3 issues, studies of adherence to the guideline rarely assessed anything beyond level 1 issues. This suggests that guideline recommendations about level 2 and level 3 issues may be too imprecise for use in evaluative studies. The drug-information compendia, on the other hand, provide detailed recommendations about level 3 issues. Revision of drug compendia may be warranted to include recommendations about all levels of drug-therapy issues. The results of intervention studies to improve drug-therapy compliance with guidelines suggest that information provided at the time of prescribing, information presented by local health professionals and information provided with a large amount of provider contact may be more likely to demonstrate significant improvements in drug therapy. We conclude that practice guidelines are a useful resource for augmenting DUR/DUE but that challenges to optimising their use include whether they can be kept current, acceptable and accessible to providers.

Counseling patients about prescribed medication: 12-year trends.

OBJECTIVES: The authors determined patients' report of prescription drug counseling activities after withdrawal of the pilot program to require patient package inserts in 1980 and implementation of Omnibus Budget Reconciliation Act of 1990 counseling requirements in 1993. METHODS: Four cross-sectional national telephone surveys were conducted in the fall of 1982, 1984, 1992, and 1994. Telephone households were chosen by random-digit dialing. Subjects had obtained a new prescription for themselves or for a family member at a retail pharmacy during the previous 4 weeks. Verbal counseling rates at physician offices and pharmacies for five information categories and the distribution of written information at those locations were determined. RESULTS: Spontaneous verbal counseling at the physician's office has increased slightly, with the largest increases focused on the delivery of side effect and precautionary information. Slightly larger increases in pharmacy-delivered information regarding directions for use and precautions have occurred. Patient questioning has remained at single digit levels at both sites. The percentage of patients receiving any written information has increased from 5% to 15% at the physician's office and from 16% to 59% at the pharmacy. CONCLUSIONS: The data indicate small increases in verbal counseling but larger increases in the delivery of written information provided at the pharmacy. In light of Healthy People: 2000 goals for patient counseling and legislation encouraging private-sector initiatives, these data should help to refocus attention on the continuing need for effective patient education interventions.

Prescription drug payment policy: past, present, and future.

The articles presented in this issue offer an array of policy-relevant studies in an area that has become increasingly important to both the public and third-party payers. Although it is believed that appropriate utilization of drugs can contribute to containing the growth of health care costs, the impact of appropriate prescribing, dispensing, and use of drugs associated with costs of hospitalizations and physician visits is generally unavailable. As new, ever-more-expensive drugs come to market, comprehensive studies of utilization, expenditures, prices, quality, and cost effectiveness will enhance the policy process.

State Medicaid pharmacy payments and their relation to estimated costs.

Although prescription drugs do not appear to be a primary source of recent surges in Medicaid spending, their share of Medicaid expenditures has risen despite efforts to control costs. As part of a general concern with prescription drug policy, Congress mandated a study of the adequacy of Medicaid payments to pharmacies. In this study, several data sources were used to develop 1991 estimates of average pharmacy ingredient and dispensing costs. A simulation was used to estimate the amounts States pay. Nationally, simulated payments averaged 96 percent of estimated costs overall but were lower for dispensing costs (79 percent) and higher for ingredient costs (102 percent).

Antihypertensive therapy for the elderly: an expert system to assist therapeutic decisions.

The prevalence of hypertension among the elderly is high. Recent multicenter studies have shown hypertension, especially isolated systolic hypertension, to be a risk factor and treatment to be effective, if individualized. In addition, the presence of multiple complicating conditions and the need for multiple medications in the elderly increases the required medical knowledge base necessary to appropriately determine antihypertensive therapy. To assist the primary provider, an expert system has been developed that provides advice on therapeutic decisions for elderly patients (greater than 65 years old and less than 85 years old). It takes into account such factors as age, sex, lifestyle, site of care, nutritional status, physiologic and pathophysiologic changes, co-existing diseases, multiple drug use, and prior antihypertensive drug exposure and response. The system user enters patient characteristics, disease states, risk factors, relevant laboratory values, and prior drug therapy. The system responds with a set of recommendations of appropriate therapy individualized for the specific patient. To further assist the process, relative costs of therapy are also included. The system, consisting of over 200 rules, is currently undergoing validation by a panel of cardiologists. It is implemented in IBM's Expert System Environment (ESE) on the IBM 4341. The authors wish to acknowledge the contribution of the ESE software by the IBM Corporation.