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The current concepts of "normal values" and "clinical reference values" in the clinical laboratory (trials for determining clinical reference values of the Tokai University Hospital).

The purposes of this commentary are 1) to summarize the problems and ambiguities that cause many clinical pathologists to discard the term "normal values"; 2) to describe and define two terms, 'normal values" and "clinical reference values", which are becoming important for clinical interpretation of laboratory data; 3) to describe a new method for estimating clinical reference ranges of blood chemistry laboratory tests performed on selected Tokai University Hospital patients; and 4) to provide a bibliography of articles that have focused attention on the conceptual problems in this field.

Blood Chemical Analysis↗

Strategic proposals for avoiding toxic interactions with drugs for clinical use during development and after marketing of a new drug--proposals for designing non-clinical and clinical studies--is the non-clinical study useful?

Since sorivudine incident has happened in Japan in 1993, an adverse drug-drug interaction has been of special meanings at each step of new drug development including the discovery step, NDA process, and on market. While it is known that several mechanisms are involved in the drug-drug interactions, the mechanisms related to drug metabolism are 1) inhibition of drug metabolizing enzymes, 2) induction of the enzymes, 3) drug absorption, 4) renal excretion, 5) hepatic transport, and 6) protein binding (displacement) interaction. In this report, proposals to avoid serious/lethal drug-drug interactions are presented with the examples. The proposals are: 1) To estimate the drug-drug interactions in consideration of the mechanisms reported so far, 2) To be especially careful for drugs with a small therapeutic index and severe/lethal toxicity, 3) To estimate the drug-drug interactions in consideration of physiological factors of patients, who receive drugs in combination, 4) Not to leave the mechanism unclear, when some data, which do not deny the critical drug-drug interactions, were obtained, and 5) To conduct the drug-drug interaction studies in humans in careful consideration of the safety.

Animals↗

Clinical effectiveness and cost effectiveness of zanamivir (Relenza): translating the evidence into clinical practice, a National Institute for Clinical Excellence view.

The UK National Institute for Clinical Excellence (NICE) is charged with the duty of providing informed guidance on clinical practice (clinical effectiveness and cost effectiveness) to patients and health professionals. The Appraisal Committee through its process of review of evidence advises NICE on the clinical effectiveness and cost effectiveness of new and existing technologies and their appropriate use within the National Health Service in England and Wales. The appraisal process takes into account both published and unpublished evidence as well as input from professional and patient and carer groups when coming to its decisions. The appraisal of a new technology often has to bridge the gap between the evidence required for licensing purposes and that needed to provide pragmatic advice to practising clinicians. The appraisal of zanamivir (Relenza) is an excellent working example of this difficult and important process.

Antiviral Agents↗

Use of hematopoietic colony-stimulating factors: comparison of the 1994 and 1997 American Society of Clinical Oncology surveys regarding ASCO clinical practice guidelines. Health Services Research Committee of the American Society of Clinical Oncology.

PURPOSE: The American Society of Clinical Oncology (ASCO) Health Services Research Committee sought to assess whether more appropriate patterns of colony-stimulating factor (CSF) use occurred after the publication of ASCO evidence-based practice guidelines in 1994 and 1996 for patients with solid tumors or lymphoma. METHODS: In 1994 and 1997, questionnaires describing clinical scenarios were mailed to ASCO members who practiced medical oncology. Physicians were asked the extent to which they preferred to use a CSF for primary prophylaxis, secondary prophylaxis, or treatment of neutropenic complications. Multiple regression analyses were used to determine predictors of overall propensity to use CSFs and, when using a CSF, propensity to support longer schedules of CSF use. RESULTS: Decreased use of CSFs was shown in the following situations: (1) treatment for febrile neutropenia without localizing signs (39% in 1994 v 29% in 1997) or with a right lower lobe infiltrate (54% v 46%); (2) primary prophylaxis with paclitaxel for ovarian cancer (20% v 11%) or cyclophosphamide, doxorubicin, and vincristine chemotherapy for small-cell lung cancer (8.4% v 4.6%); and (3) secondary prophylaxis after afebrile neutropenia following chemotherapy for germ cell tumors (44.5% v 36.0%). One third fewer physicians supported the extended use of CSFs until an absolute neutrophil count >/= 10,000/mm(3) or a WBC count >/= 10,000/mm(3) was reached, both counts serving as criteria for stopping CSF therapy. However, we observed high rates of CSF use despite ASCO guideline recommendations against use in the following clinical situations: (1) primary prophylaxis in patients at low risk of febrile neutropenia (6% v 16%); (2) secondary prophylaxis late in the course of curative and palliative therapy (80% v 53%); and (3) treatment of afebrile and uncomplicated febrile neutropenia (30% v 60%). In 1994 and 1997, fee-for-service physicians were more likely than other physicians to prefer use of CSF support while maintaining treatment dose and schedule instead of using dose-reduction strategies, and, when using a CSF, they were more likely to support longer CSF treatment schedules (P <.05 for both scenarios). CONCLUSION: Decreased use and more appropriate use of CSFs in accordance with ASCO guideline recommendations occurred from 1994 to 1997, but there remain many opportunities to reduce CSF use with no clinical harm. Many oncologists continue to support the use of CSFs in scenarios and with scheduling criteria that the guidelines and evidence do not support. ASCO's evidence-based guidelines should be linked with formal continuous quality improvement initiatives to substantially improve the quality of supportive oncology care.

Hematopoietic Stem Cells↗

Clinical examination of pelvic insufficiency during pregnancy. An evaluation of the interobserver variation, the relation between clinical signs and pain and the relation between clinical signs and physical disability.

The purpose of this study was to answer the following questions: Do clinical signs in pregnant women with pelvic pain differ from signs in those without pelvic pain? Is there variation between the test signs found by four observers? Are the clinical signs correlated to pain and physical disability? Twenty pregnant women with pelvic pain and 20 pregnant women without pelvic pain were participating. Each woman reported her own pain sensation and physical disability and each woman was examined by 4 physiotherapists independently. Sixty-one clinical tests were applied. Only 8 tests showed predominantly positive signs in the pain group. These tests showed agreement between different observers judged by a kappa coefficient > 0.40. The number of positive clinical signs was well correlated to the reported pain and physical disability. The value of an extensive examination of posture, muscles and joints on pregnant women with pelvic pain is dubious.

Activities of Daily Living↗

Program Directors' and Clinical Instructors' Perceptions of Important Clinical-Instructor Behavior Categories in the Delivery of Athletic Training Clinical Instruction.

OBJECTIVE: To investigate the perceived importance of clinical instructors' behaviors and behavior categories in the roles of program director (PD) and clinical instructor (CI) and to ascertain the relative importance of these items within each role. DESIGN AND SETTING: From the literature, we developed a questionnaire, validated by a panel of experts, to collect data regarding the perceived importance of 30 specific CI behavior statements within 5 categories (instructional, interpersonal, evaluative, professional, and personal). The instrument used in the study had a Cronbach alpha of.92. SUBJECTS: Independent groups of 75 PDs and 242 CIs from Commission on Accreditation of Allied Health Education Programs-accredited entry-level undergraduate athletic training programs returned usable surveys. MEASUREMENTS: We computed mean and variation measures for each behavior and category and analyzed these items for between-role and within-role category differences. RESULTS: Program directors and CIs differed significantly in the perceived importance of the evaluative category of CI behaviors as well as in 3 specific evaluative behaviors. Program directors and CIs did not differ in the other 4 categories. For within-role groupings, we noted significant differences of perceived importance among the behavioral categories. CONCLUSIONS: Program directors and CIs perceived all 5 categories to be very important, and they should work to demonstrate these behaviors in clinical-education settings. Collaboration between the groups enhances the understanding of role responsibility in the delivery of athletic training clinical instruction.

Journal Article↗

[Studies on clinical subsets and severity of systemic lupus erythematosus based on a 1987 questionnaire conducted in Japan--clinical analysis of the outcome and treatments in clinical subsets].

A 1987 questionnaire sponsored by the Health and Welfare Ministry concerning the clinical subsets and severity of systemic lupus erythematosus (SLE) was distributed to 93 medial facilities. A clinical analysis of the outcome and treatments was accomplished on one thousand six hundred and fourteen SLE patients fulfilling ARA criteria. The outcome was evaluated into 6 categories, namely; complete remission, incomplete remission, no change, gradual worsening, rapid worsening and unknown. Treatments included (1) anti-inflammatory drugs, (2) initial dose of prednisolone (PSL) below 29 mg/day, (3) initial dose of PSL from 30 to 59 mg/day, (4) initial dose of PSL above 60 mg/day, (5) pulse therapy, (6) immunosuppressants, (7) plasmapheresis, and (8) hemodialysis. Statistical significances were determined with ridit analysis. The severity of the disease for 1,614 SLE patients was evaluated by the judgement of each medical facility independently, separating it into 3 grades. As a result, 16.8% was evaluated as severe, 54.6% was evaluated as moderate, and 28.6% was evaluated as mild. Clinical subsets were divided into 3 categories according to the outcome; (1) those with high complete remission rates (serositis, convulsion, oral ulcers, unconsciousness, hemolytic anemia and so on), (2) those with high incomplete remission rates (lupus nephritis, digital gangrene, hypertension, peripheral neuropathy, erythema, Raynaud's phenomenon and so on), and (3) those with high rates of no change or worsening (aseptic bone necrosis, pulmonary hypertension, pneumonitis, chronic renal failure and so on). SLE patients with persistent proteinuria below 3.4 g/day, pulmonary hypertension, or pneumonitis treated with large doses of PSL such as an initial dose of PSL above 60 mg/day and/or pulse therapy had a significantly higher remission rate than those treated with small dosages of PSL. Hereafter, the establishment of modes of treatments for increasing the remission rates of intractable clinical subsets in highly desired.

Adolescent↗

Health and clinical management - comparing the clinical outcome of computerized strategies. Findings from the Section on Health and Clinical Management.

OBJECTIVES: To summarize current excellent research in the field of health and clinical management. METHODS: Synopsis of the articles selected for the IMIA Yearbook 2006. RESULTS: Current research in the field of health and clinical management analyses impact and patient outcome of both established and recently presented approaches. Usability and effects of extracting data from computerized medical records for preventive care and surveillance issues are a topic as well as strategies for detecting adverse events. CONCLUSIONS: The best paper selection in the field of health and clinical management shows examples of excellent research on assessment, strategies and concepts for computerized health information management approaches. The articles emphasize the necessity of carefully considering health information systems regarding their outcome and compatibility with clinical routine. A concerted management of knowledge about evaluated health information management approaches will advance this trend and should lead to a more evidence-based design of the underlying systems.

Awards and Prizes↗

[Japan Clinical Oncology Group for cooperative cancer clinical trials and role of the statistical center in the management of cancer clinical trials].

In 1978, clinical investigators decided to collaborate on clinical trials through a "cooperative group" mechanism in order to promote multidisciplinary treatment of cancer under the auspices of a Grant-in-Aid for Cancer Research from the Ministry and Health and Welfare. This cooperative study group was formally renamed in 1990 and became "The Japan Clinical Oncology Group (JCOG)," and its Statistical Center was housed in the National Cancer Center Hospital. This paper introduces various JCOG activities and the role of the Statistical Center.

Clinical Protocols↗

Is good clinical research practice for clinical trials good clinical practice?

This article presents results of monitoring of the recruitment process for a phase III study of a new antidepressant drug in elderly patients with depressive disorders, focusing on the peculiarities of recruitment posed by the presence of comorbidity and coadministration of medications. Data are derived from screening of 188 patients, the majority of whom lived at home, referred for trial inclusion. One hundred and seventy-one (91%) had Hamilton Rating Scale score in excess of 18 and met inclusion criteria. Only eight (4.2%) elderly depressed subjects could be recruited, after application of exclusion criteria. The trial data so obtained may be scientifically credible, but the conclusions reached by trials with very stringent exclusion criteria do not reflect the practice environment in which the product will be prescribed by clinicians. This raises questions of the relevance of good clinical research practice and good clinical practice guidelines to the reality of good clinical practice beyond the trial situation.

Aged↗

Considerations in choice of a clinical endpoint for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).

In most clinical trials of antiretroviral therapy for patients infected with HIV, the major outcome variable has been the combined clinical endpoint of any new or recurrent AIDS defining event. We review features of combined endpoints and use data from the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) to evaluate this outcome measure in terms of relevance, diagnostic certainty and sensitivity. We conclude that this endpoint is not relevant because: (i) the 19 different events constituting the combined endpoint are equally weighted in analyses even though they vary considerably in terms of risk of death; and (ii) events after the first are ignored, thus the event profile of patients is not taken into account in making treatment comparisons. We also conclude that power may be low with use of this endpoint if treatments under study do not have an immediate impact on disease progression, if some events which occur soon after randomization represent a disease process that has already begun to incubate, or if treatment differences for the various events constituting the combined endpoint are differentially effected by treatment. Since the ease and certainty of diagnosis of each of the 19 events also vary, we recommend that survival be the primary endpoint of antiretroviral trials, and that all opportunistic events experienced by patients, not just the first, be collected and summarized. Trial reports should include comparisons of incidence of each event by treatment group so that readers can rank events as they please. A single summary measure which considers severity and the entire event profile, as described here, would also be useful for assessing the impact of treatments on quality of life. Further research on approaches for weighting and combining multiple outcome measures is needed.

AIDS-Related Opportunistic Infections↗

Twelve-year clinical course of schizophrenia from 1971/73 to 1983. A longitudinal study of clinical course and a cross-sectional study 12 years after hospital or night-clinic treatment.

Two samples of 46 schizophrenic patients, one of new attendees at a night clinic in 1971-73 and the other of hospitalized patients matched for age and sex, were followed up 12 years later. Seven of the former and two of the latter had died, all from self-destructive acts. Of the survivors, one-third were rated inconspicuous with regard to psychopathology, one-fifth as conspicuous only to a psychiatrist, and only one-quarter as very conspicuous, even to a layperson. During the first 4 years the night clinic patients showed signs of an insidious chronic course; substantially fewer (17.6% compared with 28.6%) were hospitalized at the time of follow-up, though far more were receiving outpatient or semi-inpatient care. In both samples self-isolation and inadequate rehabilitation for work were marked; 72% and 62% respectively were dependent on a disability pension, and only 15% and 20% were employed at work in keeping with their training and experience. Just under half lived alone, and 30-40% had no contact with friends/acquaintances. Longitudinal analysis disclosed a marked decrease in the number and duration of overt phases and stays in hospital, progressive aggravation or residual symptoms in quiescent intervals, and similar decline in ability to work and earn a living. Covariance analysis revealed a significantly greater reduction in total hospitalization in night clinic patients.

Activities of Daily Living↗

[Herpes simplex in children. Clinical manifestations, diagnostic value of clinical signs, clinical course].

Herpetic gingivostomatitis (HGS) is the predominant manifestation of cutaneomucosal herpes in children with HSV1 primary infection before the age of 3 years. The infection is self limiting and lasts 10 to 14 days. Pain and dysphagia are particularly important during the first week of infection and may necessitate parenteral rehydratation and administration of antalgesics. HGS in the young child causes substantial morbidity leading to hospital and social costs (work stoppage for parents). The clinical course is generally benign with the exception of forms with important extension, eczema, herpeticum Kaposi-Juliusberg pustulosis observed at this age only in children with atopic dermititis. Other severe forms are observed in the neonate and immunodepressed subject, which can also be caused by HSV1. Forms with little or not clinical manifestation predominate and generally go undiagnosed, explaining the asymptomatic viral excretion observed in the saliva or other secretions (ocular, genital secretions). Despite the sterotypic nature of the clinical expression, HGS is still often undiagnosed both by general practitioners and pediatricians. This lack of diagnosis generally has few consequences due to the benign course in a few days, but the infection can have an important psychological and social leading to significant healthcare costs. Moderate and severe forms require medical care. Aciclovir should be prescribed if the diagnosis is made early (3 days) in combination with symptomatic care. Studies of the medical and economic impact of herpetic gingivostomatis should be conducted.

Acyclovir↗

[Clinical studies on chronic prostatitis and prostatitis-like syndrome. (3). Clinical re-examination of chronic bacterial prostatitis using the criteria for clinical evaluation].

In accordance with the criteria for clinical evaluation, established by the UTI research group, 43 cases of chronic bacterial prostatitis were retrospectively analyzed. The subjective symptoms were "resolved" in 18.5%, "improved" in 46.5%, and "persisted" in 34.9%. The white blood cells were "cleared" in 34.9%, "decreased" in 37.2%, and "unchanged" in 27.9%. The bacteria were "eliminated" in 51.2%, "decreased" in 16.2%, "replaced" in 11.6%, and "unchanged" in 21.0%. Overall clinical efficacy was "excellent" in 51.2%, "moderate" in 39.5%, and "poor" in 27.9%, with an overall effectiveness rate of 72.1%. Bacteria (isolated bacteria: 8 species, 52 strains) were "eradicated" in 69.2% (GNR 71.4%, GPC 66.7%), and "persisted" in 30.8%. The bacterial eradication rate was 87.5% for E. coli, 58.3% for S. epidermidis, and 75.0% for E. faecalis. The analytical results of the clinical effects, classified by characteristic factor, showed significantly better results, in the excellence rate (p less than 0.05) and the overall effectiveness rate (p less than 0.01) of primary cases as compared with relapse cases. Among the isolated bacterial species, GNR showed more favorable results in comparison with GPC but without any significant difference. Further, the results of 81.3% for E. coli, 66.7% for S. epidermidis, and 62.5% for E. faecalis, indicates no significant difference between respective bacterial species. The new quinolones showed a favorable rate of 92%, followed by 80% of ST (sulfamethoxazole-trimethoprim), and 78% of tetracyclines, with a significant difference (p less than 0.01) in comparison with the mean overall effectiveness rates of cephems, penicillins, and old quinolones.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Quinolones↗

Non-surgical management of early breast cancer in the United Kingdom: follow-up. Clinical Audit Sub-committee of the Faculty of Clinical Oncology, Royal College of Radiologists, and the Joint Council for Clinical Oncology.

Follow-up of operable breast cancer patients takes up a significant proportion of British oncologists' time, with 90% seeing 5-50 patients each week. Procedures vary greatly, but, in patients treated by surgery and radiotherapy, care is usually shared, with alternating visits to see each team. Currently, the general practitioner has sole responsibility for follow-up in less than 3% of patients. They tend to be followed up in general, rather than specialist, clinics. There is almost universal agreement that routine blood tests, radiographs and scans are not indicated as part of routine follow-up, but the role of mammography in evaluating an irradiated breast remains a source of debate. Just over a half of the oncologists surveyed order baseline mammography of both treated and contralateral breasts, usually between 6 and 12 months after local excision and radiotherapy, with further follow-up 1-3-yearly thereafter. Ten per cent of the participating oncologists never suggest follow-up mammography. Patients tend to be followed in oncology clinics at 3-4-monthly intervals for the first 2 years, 6-monthly in the third and fourth years and, thereafter, yearly. Fifteen per cent of oncologists discharge patients at 5 years, with the discharge rate rising to 43% at 10 years; around one-third modify follow-up according to the age of the patient. The aims of follow-up were seen to include detection of curable disease, but other goals were perceived as equally important (e.g. detection of iatrogenic problems, audit, counselling, education and the provision of early palliation of incurable and metastatic disease. Breast cancer is no longer seen as an absolute contraindication to either pregnancy or the use of hormone replacement therapy (HRT); however, oncologists are uncertain about the appropriate use of HRT, either alone or with tamoxifen. This audit highlights a number of research areas: the identification of the appropriate site and skill-mix for follow-up of patients; clarification of the aims and attitudes to follow-up by both patients and health care professionals; the use of breast imaging; and the role of HRT.

Age Factors↗

Transatlantic Conference on Clinical Trial Guidelines in Peripheral Arterial Disease: clinical trial methodology. Basel PAD Clinical Trial Methodology Group.

Guidelines for the clinical development of drugs in peripheral arterial disease (PAD) have been issued by the Food and Drug Administration for the United States and by the regulatory agency of the European Union for Europe. With increasing globalization, transatlantic cooperation in drug research and development is essential for the future and would be substantially facilitated by the existence of transatlantic guidelines. A conference was held in Basel, Switzerland, in November 1997 to discuss the scientific background of the existing guidelines on the basis of published evidence and the extensive knowledge of clinical investigators and experienced regulators. The meeting was attended by 52 invited experts from the United States and Europe, as well as by representatives from the 2 regulatory authorities. The main conclusions from the meeting are presented and may serve as a reference for the future development of transatlantic guidelines for the evaluation of pharmacotherapy in PAD.

Clinical Trials as Topic↗

Medical devices; clinical chemistry and clinical toxicology devices; instrumentation for clinical multiplex test systems. Final rule.

The Food and Drug Administration (FDA) is classifying instrumentation for clinical multiplex test systems into class II (special controls). The special control that will apply to the device is the guidance document entitled "Class II Special Controls Guidance Document: Instrumentation for Clinical Multiplex Test Systems." The agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. Elsewhere in this issue of the Federal Register, FDA is publishing a notice of availability of a guidance document that is the special control for this device.

Chemistry, Clinical↗