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PubMed1982

Protection of human subjects: first biennial report on the adequacy and uniformity of federal rules and policies, and their implementation for the protection of human subjects in biomedical and behavioral research; Report of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Department of Health and Human Services. Notice of report for public comment.

On November 8, 1978, the Public Health Service Act (Pub. L. 95-622) was amended, thereby creating the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. One of the charges of the Commission was to biennially report to the President, the Congress, and appropriate Federal agencies on the protection of human subjects of biomedical and behavioral research. In carrying out the above, the Commission was directed to include a review of the adequacy and uniformity (1) of the rules, policies, guidelines, and regulations of all Federal agencies regarding the protection of human subjects of biomedical or behavioral research which such agencies conduct or support, and (2) of the implementation of such rules, policies, guidelines, and regulations by such agencies, and may include such recommendations for legislation and administrative action as the Commission deems appropriate.

Adult↗
PubMed2002

Environmental risk assessment for new human pharmaceuticals in the European Union according to the draft guideline/discussion paper of January 2001.

Since 1993, an environmental risk assessment (ERA) for a new drug application has been stipulated by EU Directive 93/39/EEC amending Directive 65/65/EEC. In early 2001, after several unpublished draft versions for an ERA guideline, a draft guideline/discussion paper for an ERA for non-GMO-containing drugs was published by the European Medicines Evaluation Agency (EMEA). The draft guideline describes a step-wise, tiered procedure for the ERA. The first tier consists of deriving a crude predicted environmental concentration (PEC) in the aquatic compartment for the active pharmaceutical ingredient (API) or its major metabolites, based on predicted amounts used and specific removal rates in sewage treatment or surface waters. If this crude PEC is <0.01 microg/l and no environmental concerns are apparent, no further assessment is deemed necessary. Else, in the second tier, a crude predicted no-effect level (PNEC) for the aquatic compartment is to be extrapolated by dividing the lowest 50%-effect concentration from acute ecotoxicity tests with algae, daphnia or fish (EC(50), LC(50)) by an assessment factor (usually 1000). If the ratio PEC/PNEC is <1, no further assessment is deemed necessary. Lastly, in the third tier, further considerations on a case-by-case basis are needed. This may encompass refining the environmental fate information and thereby the PEC, considering further environmental compartments and their respective PECs (up to and including field studies), but also refining the PNEC. While the ERA addresses mainly the API, excipients of the formulated drug should be considered as well. In the case of medicinal products, the benefit for patients has relative precedence over environmental risks, meaning that even in the case of an unacceptable residual risk for new drugs after third-tier considerations, prohibition of a new API is not taken into consideration. Instead, possible mitigating or precautionary safety measures may consist of specific product labelling (i.e. package leaflets for the patients regarding returning and proper disposal of unused medicines), restricted use through in-hospital or in-surgery administration under supervision only, or the recommendation of environmental analytical monitoring up to ecological field studies.

Drug-Related Side Effects and Adverse Reactions↗
PubMed2002

Environmental risk assessment for new human pharmaceuticals in the European Union according to the draft guideline/discussion paper of January 2001.

Since 1993, an environmental risk assessment (ERA) for a new drug application has been stipulated by EU Directive 93/39/EEC amending Directive 65/65/EEC. In early 2001, after several unpublished draft versions for an ERA guideline, a draft guideline/discussion paper for an ERA for non-GMO-containing drugs was published by the European Medicines Evaluation Agency (EMEA). The draft guideline describes a step-wise, tiered procedure for the ERA. The first tier consists of deriving a crude predicted environmental concentration (PEC) in the aquatic compartment for the active pharmaceutical ingredient (API) or its major metabolites, based on predicted amounts used and specific removal rates in sewage treatment or surface waters. If this crude PEC is <0.01 microg/l and no environmental concerns are apparent, no further assessment is deemed necessary. Else, in the second tier, a crude predicted no-effect level (PNEC) for the aquatic compartment is to be extrapolated by dividing the lowest 50% effect concentration from acute ecotoxicity tests with algae, daphnia or fish (EC(50), LC(50)) by an assessment factor (usually 1000). If the ratio PEC/PNEC is <1, no further assessment is deemed necessary. Lastly, in the third tier, further considerations on a case-by-case basis are needed. This may encompass refining the environmental fate information and thereby the PEC, considering further environmental compartments and their respective PECs (up to and including field studies), but also refining the PNEC. While the ERA addresses mainly the API, excipients of the formulated drug should be considered as well. In the ease of medicinal products, the benefit for patients has relative precedence over environmental risks, meaning that even in the ease of an unacceptable residual risk for new drugs after third tier considerations, prohibition of a new API is not taken into consideration. Instead, possible mitigating or precautionary safety measures may consist of specific product labelling (i.e. package leaflets for the patients regarding returning and proper disposal of unused medicines), restricted use through in-hospital or in-surgery administration under supervision only, or the recommendation of environmental analytical monitoring up to ecological field studies.

Drug-Related Side Effects and Adverse Reactions↗
PubMed2005

Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors.

PURPOSE: To assess the maximum-tolerated dose, toxicity, and pharmacokinetics of DE-310, a macromolecular prodrug of the topoisomerase I inhibitor exatecan (DX-8951f). in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients received DE-310 as a 3-hour infusion once every 2 weeks (dose, 1.0-2.0 mg/m(2)) or once every 6 weeks (dose, 6.0-9.0 mg/m(2)). Because pharmacokinetics revealed a drug terminal half-life exceeding the 2 weeks administration interval, the protocol was amended to a 6-week interval between administrations also based on available information from a parallel trial using an every 4 weeks schedule. Conjugated DX-8951 (the carrier-linked molecule), and the metabolites DX-8951 and glycyl-DX-8951 were assayed in various matrices up to 35 days post first and second dose. RESULTS: Twenty-seven patients were enrolled into the study and received a total of 86 administrations. Neutropenia and grade 3 thrombocytopenia, and grade 3 hepatotoxicity with veno-occlusive disease, were dose-limiting toxicities. Other hematologic and nonhematologic toxicities were mild to moderate and reversible. The apparent half-life of conjugated DX-8951, glycyl-DX-8951, and DX-8951 was 13 days. The area under the curve ratio for conjugated DX-8951 to DX-8951 was 600. No drug concentration was detectable in erythrocytes, skin, and saliva, although low levels of glycyl-DX-8951 and DX-8951 were detectable in tumor biopsies. One patient with metastatic adenocarcinoma of unknown primary achieved a histologically proven complete remission. One confirmed partial remission was observed in a patient with metastatic pancreatic cancer and disease stabilization was noted in 14 additional patients. CONCLUSIONS: The recommended phase II dose of DE-310 is 7.5 mg/m(2) given once every 6 weeks. The active moiety DX-8951 is released slowly from DE-310 and over an extended period, achieving the desired prolonged exposure to this topoisomerase I inhibitor.

Adult↗
PubMed1976

Food safety--then and now. A Bicentennial study.

Although this is our Bicentennial year, effective measures to insure food safety date back less than a century. The first efforts toward reform were begun by Accum in England early in the nineteenth century, but they did not bear fruit there--in even a beginning form--until 1875, when Parliament passed the Sales of Food and Drug Act. Legislation came even later in the U.S.--not until the first Pure Food and Drugs Act became law in 1906, largely due to the unswerving efforts for almost twenty years of Harvey W. Wiley. Today, the scientific approach is applied in developing criteria for judging the safety of food and for regulations to insure that healthful, safe food reaches the consumer. Amendments to this law in 1938 and 1958 have further strengthened the protection the public is provided in its food supply. Today, the substances on the "GRAS" list are being examined individually to determine their safety when used in foods. However, the legalistic invoking of absolutes, as in the Delaney Clause of the 1958 amendments, goes beyond the limits of common sense. The challenge is to insure the benefits of science and technology without the loss of basic individual freedom.

Community Participation↗
PubMed1999

Pitfalls in cytological diagnosis of autoimmune thyroiditis.

The aims of this study are to document pitfalls in cytologic diagnosis of autoimmune thyroiditis (AT) and highlight possible ways to minimize them. One hundred consecutive thyroid aspirates with features diagnostic or suggestive of AT, performed and reported by the first author, were included in the study. Follow-up was traced and cytologic features responsible for indecisiveness were re-assessed in those reported as suggestive of AT. The features were then correlated with the results of serologic and thyroid function tests and clinical features, and an attempt was made to amend the final diagnosis using an integrated approach. Seventy eight were diagnostic and 22 were suggestive of AT. In the latter 22, features responsible for the indecisiveness were: cytologic atypia, in the form of nuclear enlargement, irregularity and grooves and altered chromatin texture, in 14 (64%); nucleoli with suspicion of a coexisting neoplasm in three (13.6%), two of which showed epithelial preponderance, crowding and discohesion; sparse inflammation in four (18%); a predominant lymphoid population without epithelial cells resembling a reactive lymph node in one (4.5%); co-existing toxic features in two (9%); and scanty smears in one (4.5%). Eighteen of the 22 suspected of AT had follow-up. Six had been assessed histologically; three with features suspicious of a neoplasm were diagnosed respectively as a papillary carcinoma (PC), Hurthle cell carcinoma (HCC) and a multinodular goitre (MNG) with degenerate changes. The other three were confirmed as AT; one with cytologic atypia, one with sparse inflammation and the third as cytologically resembling a reactive lymphnode. In ten of the remaining 12, the final diagnosis could be revised following an integrated approach with possible reduction of the indecisiveness. Potential pitfalls are: cytologic atypia occurring in AT; abundance or scarcity of background inflammation; low cell yield; and co-existing toxicity and malignancies. Epithelial preponderance over inflammation, nuclear crowding, severe atypia and cell discohesion should raise the possibility of a neoplasm in spite of other features of AT. Awareness of possible pitfalls and adopting an integrated approach, especially in difficult situations, will minimize pitfalls.

Adenocarcinoma↗
PubMed2004

Sexual harassment in medical education: liability and protection.

The prevalence and frequency of sexual harassment in medical education is well documented. On the graduation questionnaire administered by the Association of American Medical Colleges in 2003, 15% of medical students reported experiences of mistreatment during medical school. On items that specifically address sexual mistreatment, over 2% of students reported experiencing gender-based exclusion from training opportunities, and unwanted sexual advances and offensive sexist comments from school personnel. Sexual harassment of medical trainees by faculty supervisors is obviously unethical and may also be illegal under education discrimination laws. In two cases in 1998 and 1999, the U.S. Supreme Court clarified that schools may be held liable under Title IX of the Education Amendments of 1972 for the sexual harassment of their students. In 2001, the Office of Civil Rights of the Department of Education released revised policy guidelines on sexual harassment that reflect the Supreme Court rulings. Medical school administrators should undertake formal assessments of the educational environment in their training programs as a first step toward addressing the problem of sexual harassment. The authors recommend that medical schools implement measures to both prevent and remedy sexual harassment in their training programs. These constructive approaches include applying faculty and student education, establishing a system for notification and response, and creating an institutional structure to provide continuous evaluation of the educational environment.

Clinical Clerkship↗
PubMed1984

The emergency medical system in Japan.

In Japan, ambulance service was originated by the Osaka Branch Office of the Japan Red Cross in 1931. In 1933 the fire department organ of Yokohama started ambulance service. It was, however, without any legal requirements. Since the early 1960s, Japan has experienced a rapid development of industry and economy, so that traffic accidents have increased, necessitating a nationwide ambulance service system. In October 1961 the Director-General of the Fire Defense Agency organized the Fire Defense Council to study the problem of ambulance service. In response, the Fire Defense Act was amended in 1963, assigning ambulance service responsibilities to Fire Defense organs. During 1982 total ambulance runs numbered 2,125,447, and the total number of transported persons was 2,049,487. Response time is excellent in Japan. More than 50% of persons who called an ambulance could get help within five minutes. First-aid management was given to 56% of total transported persons. Of these, temperature regulation was most often administered, followed by oxygen inhalation, dressing, and hemostasis. Currently, 2,965 (91.1%) municipalities provide ambulance services to 98.3% of the population. The Japanese emergency medical system has serious problems, however, such as an inadequate number of general hospitals and a flood of nonemergent patients. To alleviate such problems, the Ministry of Health and Welfare developed the critical emergency transfer system in 1977.

Ambulances↗
PubMed2003

New trends in the development of occupational exposure limits for airborne chemicals in China.

Occupational exposure limits (OELs) are well established in many countries, which serve occupational professionals as benchmarks of industrial hygiene practice at workplaces worldwide. Starting in the mid-1950s, the central government of China began promulgating OELs for hazardous substances at workplaces. This paper discusses the historical basis, philosophical principles and schematic protocols of developing and setting OELs in China. The underlying principles include: (1) protection of human health being the first and the most important criterion; (2) the use of quantitative epidemiological studies in humans being given top priority; (3) integration and full use of all information sources, including animal experimental data for new chemicals or chemicals with new toxicity concerns; (4) considerations of socioeconomic and technological feasibilities in the country; and (5) amending existing standards based on new evidence. The strategy of the World Health Organization's "Two-step Procedure" is applied to convert health-based recommendations to law-based operational OELs, with considerations for national technological and socioeconomic conditions and priorities. As a result of the recent passage of the new law Occupational Diseases Prevention and Control Act of the People's Republic of China (ODPCAct), an official document Occupational Exposure Limits for Hazardous Agents in the Workplace containing a comprehensive list of new and amended OELs has been issued, which has now become one of the most essential regulations affiliated with the ODPCAct. This paper provides a brief summary of the salient features of the new law ODPCAct and the principles and processes of developing or amending OELs. This paper also discusses the challenges that lie ahead in enforcing the new regulations in China.

Air Pollutants, Occupational↗
PubMed2001

Factors influencing rates and products in the transformation of trichloroethylene by iron sulfide and iron metal.

Batch experiments were performed to assess (i) the influence of pH, solution amendments, and mineral aging on the rates and products of trichloroethylene (TCE) transformation by iron sulfide (FeS) and (ii) the influence of pretreatment of iron metal with NaHS on TCE transformation rates. The relative rates of FeS-mediated transformation of TCE to different products were quantified by branching ratios. Both pseudo-first-order rate constants and branching ratios for TCE transformation by FeS were significantly influenced by pH, possibly due to a decrease in the reduction potential of reactive surface species with increasing pH. Neither Mn2+, expected to adsorb to FeS surface S atoms, nor 2,2'-bipyridine, expected to adsorb to surface Fe atoms, significantly influenced rate constants or branching ratios. FeS that had been aged at 76 degrees C for 3 days was completely unreactive with respect to TCE over 6.5 months, yet this aged FeS transformed hexachloroethane to tetrachloroethylene with a rate constant only slightly lower than that for nonaged FeS. This finding suggests that the oxidation state of iron sulfide minerals in the environment will strongly influence the potential for intrinsic remediation of pollutants such as TCE. Treatment of iron metal with bisulfide significantly increased the pseudo-first-order rate constant for TCE transformation at pH 8.3. This effect was attributed to formation of a reactive FeS coating or precipitate on the iron surface.

Adsorption↗
PubMed2002

Health Insurance Portability and Accountability Act of 1996 (HIPAA): a provider's overview of new privacy regulations.

When it enacted The Health Insurance Portability and Accountability Act of 1996, Congress mandated establishment of privacy regulations covering individual health information. Title II of HIPAA, the Privacy Rule that became effective on April 14, 2001, offers Americans the first-ever set of comprehensive protections against the unintended and/or inappropriate disclosure of personal health information. Provisions of the Privacy Rule and its associated regulations include patient control over the use of health information, patient rights to information on the disclosure policies of the health-care provider, patient rights to review and amend one's medical information, standards for limiting the scope of data disclosed to other health-care providers, and penalties for noncompliance with the law. This paper presents a summary of the need for protection of personal health information and an overview of the provisions of this legislative foundation for protecting personal health records--the HIPAA Privacy Rule.

Confidentiality↗
PubMed1980

[Relation of the survival of kidney transplants to their initial functional integrity].

The influence of the initial functional capacity of renal transplants on the term of their survival was studied in 107 patients who were subjected to 118 transplantations of cadaveric kidneys. If the transplant function was restored within the first days after the operation 61% of the transplants were functioning during a year. In cases with a delayed function resulting from acute insufficiency of the transplanted kidney the good functioning was observed in 28% of all the transplants. The data obtained show the importance of further studies of the ways of the amendment of the quality of kidney transplants.

Adolescent↗
PubMed1996

Pharmaceutical trials in general practice: the first 100 protocols. An audit by the clinical research ethics committee of the Royal College of General Practitioners.

OBJECTIVE: To assess the outcome of 100 general practice based, multicentre research projects submitted to the ethics committee of the Royal College of General Practitioners by pharmaceutical companies or their agents between 1984 and 1989. DESIGN: Analysis of consecutive submitted protocols for stated objectives, study design, and outcomes; detailed review of committee minutes and correspondence in relation to amendment and approval; assessment of final reports submitted at conclusion of studies. SUBJECTS: 82 finally approved protocols, embracing 34,523 proposed trial subjects and 1195 proposed general practice investigators. MAIN OUTCOME MEASURES: Success at enrolling subjects and investigators; commencement and completion data; validity of final report's assessment of efficacy, safety, tolerability, and acceptability; and method of use and dissemination of findings. RESULTS: 18 studies were not approved and 45 had to be amended. Randomised controlled trials comprised 46 of the original submissions. Remuneration considerations, inadequate information or consent sheets, pregnancy safety, the need to discontinue existing therapy, and suboptimal scientific content were major reasons for rejecting studies or asking for amendments. Of the 82 approved studies 8 were not started. Shortfalls of investigators (of 39%) and trial subjects (of 37%) and an overall 23% withdrawal rate were responsible for a significant incidence of inconclusive results. Within the six year follow up interval, only 19 of the studies had been formally published. CONCLUSIONS: This audit identified substantial ethical concerns in the process of approving multicentre general practice pharmaceutical research.

Clinical Protocols↗
PubMed2005

Bioremediation of oil refinery sludge by landfarming in semiarid conditions: influence on soil microbial activity.

Bioremediation of a refinery sludge containing hydrocarbons in a semi-arid climate using landfarming techniques is described. The objective of this study was to assess the ability of this technique to reduce the total hydrocarbon content added to the soil with the refinery sludge in semiarid climate (low rain and high temperature). In addition, we have evaluated the effect of this technique on the microbial activity of the soil involved. For this, biological parameters (carbon fractions, microbial biomass carbon, basal respiration and ATP) and biochemical parameters(different enzymatic activities) were determined. The results showed that 80% of the hydrocarbons were eliminated in eleven months, half of this reduction taking place during the first three months. The labile carbon fractions, MBC, basal respiration and ATP of the soils submitted to landfarming showed higher values than the control soil during the first months of the process, although these values fell down by the end of the experimental period as the hydrocarbons were degraded by mineralisation. All the enzymatic activities studied: oxidoreductases such as dehydrogenase activity, and hydrolases of C(beta-glucosidase activity) and N Cycle (urease and protease) showed higher values in the soils amended with the refinery sludge than in the control. As in the case of the previous parameters, these value fell down as the bioremediation of the hydrocarbons progressed, many of them reaching levels similar to those of the control soil after eleven months.

Biodegradation, Environmental↗
PubMed2000

Visual dominance in amending the directional parameter of feedforward control.

The authors examined visual dominance between trials in which the movement program was amended (i.e., off-line processing). Weighting between visual and proprioceptive feedback was examined in a trial-by-trial analysis of the directional parameter of feedforward control. Eight participants moved a cursor to a target displayed on a computer screen by manipulating a hand-held stylus on a digitizing tablet. In the first 30 trials, the cursor followed the stylus movement (practice condition). In the next 30 trials, the directional error of the stylus movement was presented in the opposite direction (reversal condition). Subjects knew the presence and the nature of the reversal. In the last 10 trials, the reversal was withdrawn (transfer condition). Directional error of feedforward control was relatively small in the practice condition, and it increased gradually in 1 of 2 directions as trials proceeded in the reversal condition. Positive aftereffect was observed in the transfer condition. A constant increment of the directional error indicated that both visual and proprioceptive feedback are registered, with higher weight on vision, and that weighting between those inputs is determined automatically or is fixed without any strategic control.

Adult↗
PubMed2006

Smallpox Vaccine Injury Compensation Program: administrative implementation. Adoption of interim final rule as final rule with amendments.

This document adopts the Smallpox Vaccine Injury Compensation Program (the Program) Administrative Implementation Interim Final Rule as the Final Rule with amendments, as follows: explains how the term "child" survivor is defined; updates the effective period of the Secretary's Declaration Regarding Administration of Smallpox Countermeasures (the Declaration); corrects an error in Sec. 102.20(d) to clarify that one of the Smallpox (Vaccinia) Vaccine Injury Table requirements to establish a covered Table injury is the first symptom or manifestation of onset of the injury in the Table time period specified; reflects the change in name from the Special Programs Bureau to the Healthcare Systems Bureau; provides the new address of the Bureau's Associate Administrator, and the new address of the Program Office; clarifies that no payments are authorized for fees or costs of personal representatives, including those of attorneys; and corrects a typographical error in Sec. 102.83(c) to make clear that the Secretary determines the timeframe for submission of required documentation.

Compensation and Redress↗
PubMed2001

Oral hygienists' education in transition.

In 1996 the Dental Faculty of the University of the Western Cape introduced a modular curriculum for Oral Hygiene students. The aim was to change from a subject-based to an outcomes-based programme, which would emphasise the competencies of hygienists. The development of this programme has meant ongoing evaluation and therefore amendments and revisions have been made throughout the course. This curriculum could be re-registered with the South African Qualifications Authority (SAQA) which describes competencies for the eight main level descriptors. This new approach to teaching allows for a laddered approach to training with intermediate exit qualifications. Oral hygienists' would thus for the first time have a career path in the oral health profession as it allows them to proceed from a Diploma to a Degree and to have the prospect of doing a Masters Degree.

Clinical Competence↗