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PubMed1998

A systematic review of the skeletal effects of estrogen therapy in postmenopausal women. II. An assessment of treatment effects.

PURPOSE: To combine the results of randomized controlled trials to provide overall estimates of the effect of estrogen treatment on fracture rates and measures of bone mass. DATA SOURCES: Articles on estrogen treatment for osteoporosis published between 1977 and 1995 were identified. STUDY SELECTION: Studies selected were randomized controlled trials of the efficacy of estrogens in preventing loss of bone mass or fractures in postmenopausal women. DATA EXTRACTION: Data extraction and quality assessment were performed in duplicate, with assistance of a manual. Raters were blinded as to authors and their affiliations and the publication details. With estimates of bone mass, the treatment effect size was defined as the difference in the mean annual change in bone mass between the treatment and control groups divided by the pooled standard deviation for change. In the case of fractures, efficacy was measured as the reduction in the numbers of individuals experiencing new fractures with treatment. Effect sizes were pooled using the random effects model. RESULTS: Thirty-seven studies met the criteria for inclusion in the systematic review. Only one small secondary prevention trial contained evaluable data on vertebral fractures. This study found a fracture relative risk of 0.63 (95% confidence interval, CI 0.28-1.43) with estrogen treatment. There was more information on the effects of treatment on bone mass. Overall effect sizes ranged between 0.5 and 2.5 standard deviation (SD) units for change. A dose-response relationship was apparent but high doses of estrogens were not associated with effect sizes greater than those observed with recommended doses. There was no significant difference in efficacy between transdermal and oral administration of estrogens. Pooling of paired data from secondary prevention studies indicated that treatment effect sizes were smaller at the hip (0.92, 95% CI 0.3-1.5 SD units) than at the spine (2.1, 95% CI 0.9-3.3 SD units). No significant effects of co-intervention with calcium, progestogens or androgens were seen, although an additive effect of higher doses of calcium could not be ruled out. CONCLUSIONS: Clear-cut effects of estrogens in attenuating the postmenopausal decline in estimated bone mass were apparent in this literature. However, the trials were short-term and provide inadequate evidence on the effects of treatment on fracture risk.

Dose-Response Relationship, Drug↗
PubMed2003

Manual versus powered toothbrushing for oral health.

BACKGROUND: Specific oral bacteria, generically known as "dental plaque" are the primary cause of gingivitis (gum disease) and caries. The removal of dental plaque is thought to play a key role in the maintenance of oral health. There is conflicting evidence for the relative merits of manual and powered toothbrushing in achieving this. OBJECTIVES: To compare manual and powered toothbrushes in relation to the removal of plaque, the health of the gingivae, staining and calculus, dependability, adverse effects and cost. SEARCH STRATEGY: We searched the Cochrane Oral Health Group's Trials Register (to 22/8/02); Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2002); MEDLINE (January 1966 to week 5 2002); EMBASE (January 1980 to week 3 July 2002) and CINAHL (January 1982 to June 2002). Manufacturers of powered toothbrushes were contacted for additional published and unpublished trials. SELECTION CRITERIA: Trials were selected if they met the following criteria: design-random allocation of participants; participants-general public with uncompromised manual dexterity; intervention- supervised manual and powered toothbrushing for at least four weeks; primary outcomes-the change in plaque and gingivitis over that period. DATA COLLECTION AND ANALYSIS: Six reviewers independently extracted information in duplicate. Indices for plaque and gingivitis were expressed as standardised values for each study. The effect measure for each meta-analysis was the standardised mean difference (SMD) with the appropriate 95% confidence intervals (CI) using random effect models. Potential sources of heterogeneity were examined, along with sensitivity analyses for the items assessed for quality and publication bias. MAIN RESULTS: Twenty-nine trials, involving 2,547 participants, provided data for the meta-analysis. Brushes that worked with a rotation oscillation action removed more plaque and reduced gingivitis more effectively than manual brushes in the short and long term. For plaque at one to three months the SMD was -0.44 (95% CI: -0.66 to -0.21), for gingivitis SMD -0.44 (95% CI: -0.72, -0.15). These represented an 11% reduction on the Quigley Hein plaque index and a 6% reduction on the Löe and Silness gingival index. At over three months the effects were SMD for plaque -1.15 (95% CI: -2.02,-0.29) and SMD for gingivitis -0.51 (95% CI: -0.76, -0.25). These represented a 7% reduction on the Quigley Hein Plaque Index and a 17% reduction on the Ainamo Bay Bleeding on Probing Gingival Index. The heterogeneity found in these meta-analyses for short term trials was caused by one trial that had exceptionally low standard deviations. Sensitivity analyses revealed the results to be robust when selecting trials of high quality. There was no evidence of any publication bias. No other powered brush designs were consistently superior to manual toothbrushes. In these trials, data on cost, reliability and side effects were inconsistently reported. Those side effects that were reported on in the trials were localised and temporary. REVIEWER'S CONCLUSIONS: Powered toothbrushes with a rotation oscillation action achieve a modest reduction in plaque and gingivitis compared to manual toothbrushing. Observation of methodological guidelines and greater standardisation of design would benefit both future trials and meta-analyses.

Dental Devices, Home Care↗
PubMed2003

Update on drug-related problems in the elderly.

BACKGROUND: Although pharmacotherapy for the elderly can treat diseases and improve well-being, its benefits can be compromised by drug-related problems. OBJECTIVE: This article reviews recent publications concerning drug-related problems in the elderly, as well as articles describing the development of 3 sets of quality indicators for medication use in the elderly. METHODS: Relevant articles were identified through a search of MEDLINE (2002-March 2003) for articles on drug-related problems, inappropriate prescribing, and adverse drug events in the elderly. RESULTS: The review included 7 articles published in 2002 and 2003. A study in ambulatory elderly persons reported that approximately 5.0% of patients had > or =1 adverse drug event within the previous year. Another study found that approximately 20.0% of ambulatory elderly persons used > or =1 inappropriate drug, as defined by drug utilization review (DUR) criteria, with drug-disease interactions and duration of use being the most common drug-related problems. A third study involving elderly individuals in assisted living facilities found that 16.0% used > or =1 inappropriate drug, as defined by the Beers criteria. Another study examined whether inappropriate drug use, as defined by the Beers or DUR criteria, was associated with death or a decline in functional status; it found that only use of drugs defined as inappropriate by DUR criteria (particularly those drugs associated with drug-drug or drug-disease interactions) was associated with a decline in the ability to perform basic self-care. Three studies, 1 from the United States, 1 from the United Kingdom, and 1 from Canada, described consensus development of quality indicators for drug use in the elderly, including drugs to avoid, maximum daily dose, drug duplication, limits on duration of use, drug-drug and drug-disease interactions, need for drug monitoring, underuse of necessary drugs to treat or prevent common problems, and inappropriate drug-administration technique. CONCLUSIONS: Drug-related problems are common in elderly patients. Data from recently published studies provide guidance to practitioners and directions for future research.

Age Factors↗
PubMed2026

Systematic Review of Pharmacologic Treatment for Migraine Prevention in Adults: Report of the AAN Guidelines Subcommittee and the American Headache Society.

BACKGROUND AND OBJECTIVES: This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS: A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS: A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION: This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

Humans↗
PubMed2006

Surgical Infection Society guideline: prophylactic antibiotic use in open fractures: an evidence-based guideline.

BACKGROUND: Prolonged courses of broad-spectrum antibiotics are often cited as the standard of care for prevention of infective complications of open fractures. The origins of these recommendations are obscure, however, and multi-drug-resistant systemic infections attributable to antibiotic overuse are common life-threatening problems in current intensive care unit practice. OBJECTIVE: To review systematically the effects of prophylactic antibiotic administration on the incidence of infections complicating open fractures. DATA SOURCES: Computerized bibliographic search of published research and citation review of relevant articles. STUDY SELECTION: All published clinical trials claiming to evaluate, or cited elsewhere as being authoritative regarding, the role of antibiotics in open fracture management were identified and then evaluated according to published guidelines for evidence-based medicine. Only small studies (<20 patients), practice surveys, pharmacokinetic studies, and reviews or duplicative publications presenting primary data already considered were excluded from analysis. DATA EXTRACTION: Information on demographics, study dates, fracture grade, antibiotic type, duration and route of administration, surgical interventions, infection-related outcomes, and the methodologic quality of the studies was extracted by the authors. The primary results were submitted to the Therapeutic Agents Committee of the Surgical Infection Society for review prior to creation of the final consensus document. DATA SYNTHESIS: Current antibiotic management of open fractures is based on a small number of studies that generally are more than 30 years old and do not reflect current management priorities in trauma and critical care. With a few noteworthy exceptions, these primary studies suffer from a variety of methodologic problems, including co-mingling of prospective and retrospective data sets, absence of or inappropriate statistical analysis, lack of blinding, or failure of randomization. CONCLUSIONS: The data support the conclusion that a short course of first-generation cephalosporins, begun as soon as possible after injury, significantly lowers the risk of infection when used in combination with prompt, modern orthopedic fracture wound management. There is insufficient evidence to support other common management practices, such as prolonged courses or repeated short courses of antibiotics, the use of antibiotic coverage extending to gram-negative bacilli or clostridial species, or the use of local antibiotic therapies such as beads. Large, randomized, blinded trials are needed to prove or disprove the value of these traditional approaches. Such trials should be performed in patients with high-grade fractures who (1) are well-stratified according to the degree of local injury and (2) undergo standardized fracture and wound management. Trials also must be powered to study the effects of extended antibiotic coverage on nosocomial infections. Antibiotic regimens confirmed to improve local fracture outcomes in such studies could then be used rationally, balancing the risks of local fracture-related infections and of multi-drug-resistant systemic infections to achieve optimal global outcomes.

Antibiotic Prophylaxis↗
PubMed2003

Indocyanine green angiography in chorioretinal diseases: indications and interpretation: an evidence-based update.

UNLABELLED: TOPIC/PURPOSE: To assess the clinical usefulness and relevance of indocyanine green angiography (ICG) in the investigation of chorioretinal disorders and assess specifically in what conditions it may add useful information to that obtained using standard fluorescein angiography. CLINICAL RELEVANCE: Many publications on ICG have appeared in recent years touting its use in ophthalmology. These publications have led to increasing use of this technique and to its application in numerous retinal diseases in which the fluorescein angiographic findings have been thoroughly described. METHODS/LITERATURE REVIEWED: During this systematic literature review, we identified and reviewed a total of 376 articles, from among which we selected 92 that we considered most relevant to our purpose of evaluating published evidence as to the efficacy of ICG. We excluded many articles with weak study designs and those that simply duplicated previously published information. Our literature search used PubMed and was confined to articles in English or that included an English abstract. RESULTS: Our systematic review suggests that ICG has relatively few specific indications for use as justified by previously published peer-reviewed studies. In keeping with the requirements for this Journal's evidence-based articles, we have divided our clinical recommendations for the use of ICG into three categories: (A) strongly recommended and supported by strong evidence; (B) recommended with moderately strong supporting evidence; (C) not recommended at present because supported only by anecdotal or group consensus evidence. We highly recommended ICG for (1) identification of polypoidal choroidal vasculopathy, (2) occult choroidal neovascularization, (3) neovascularization associated with pigment epithelial detachments, and (4) recurrent choroidal neovascular membranes. These are all conditions in which ICG contributes to the identification of lesions that may be treatable. We recommend ICG with some enthusiasm for identifying feeder vessels in age-related macular degeneration, choroidal neovascular membranes, chronic central serous retinopathy, multiple evanescent white dot syndrome, vasculitis, acute multifocal placoid pigment epitheliopathy, Vogt-Koyanagi-Harada syndrome, macular lesions associated with angioid streaks, and birdshot retinopathy. In all these conditions, ICG may help establish a diagnosis and provide some useful guidance for therapy. At present, we do not recommend ICG for scleritis and posterior scleritis, drusen differentiation, Behçet's disease, or sarcoidosis, because it has not been demonstrated to add useful clinical information. CONCLUSIONS: ICG, although now a well established technique, has clear advantage over fluorescein angiography in relatively few chorioretinal disorders. It has, however, contributed to the understanding of pathologic processes in many ocular diseases. As yet, no published randomized controlled clinical trials show any benefit to the use of ICG in the management of any specific ocular disease.

Choroid↗
PubMed2006

Home-based chemically-induced whitening of teeth in adults.

BACKGROUND: During the last decade tooth whitening products have become widely available in the USA for sale over-the-counter or dispensed by dentists for use at home. With the current rapid growth in demand for tooth whitening it is imperative that the dental community base its recommendations to patients on sound scientific evaluations conducted in well-designed and independent studies. OBJECTIVES: To evaluate the effectiveness (versus a placebo or another active product) and side effects of over-the-counter or dentist-dispensed chemically-based tooth whitening products designed for home use. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 3); MEDLINE (January 1966 to September week 2 2005); and EMBASE (1988 to week 39 2005). The tables of content of selected dental journals published since 1995 were searched for additional references. Written requests for additional studies and information were mailed to experts in this area of research. After a final set of studies was identified, the list of references reported in the included reports was reviewed to identify additional studies. Studies published in English and non-English were considered in this review. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials of dentist-dispensed or over-the-counter tooth whitening products with a chemical action (rather than abrasive action), for home use. DATA COLLECTION AND ANALYSIS: Screening of titles and abstracts, data extraction and quality assessment were undertaken independently and in duplicate. MAIN RESULTS: A total of 416 articles were identified, 25 of which met the inclusion criteria and presented data that could be used in the analysis. All included trials measured effectiveness immediately after 2 weeks of product application. Only 13 studies reported outcome data 1 week after the 2-week application period, and of those only six reported outcome data after 1 month or longer. Four of the included trials were assessed as at moderate risk of bias and the remainder at high risk of bias. All trials were sponsored by the manufacturers of tooth whitening products. Six trials compared different whitening products (gel in trays, paint-on films and whitening strips) with placebo/no treatment and all analyses showed the products to be effective, although most comparisons were based on single trials. Nineteen trials compared different whitening products with each other. There was only one meta-analysis which included more than one trial which showed statistically significant differences between the different whitening products. Strips (5.5% to 6.5% hydrogen peroxide(HP)) are more effective than gel in tray at 10% carbamide peroxide (CP) mean difference 1.82 (95% confidence interval (CI) 0.26 to 3.38). All of these trials were assessed as of high risk of bias. 'Mild' to 'moderate' tooth sensitivity and gingival irritation were the most common side effects. The whitening strips and products with high concentrations of HP caused more users to complain from tooth sensitivity. The protocols for preparation of participants prior to bleaching were inconsistent among the studies. Data on baseline scores of whiteness were not reported by the majority of the studies. The current evidence base on tooth whitening products suffers from methodological and publication biases. AUTHORS' CONCLUSIONS: There is evidence that whitening products work when compared with placebo/no treatment. There are differences in efficacy between the products, mainly due to the levels of active ingredients, hydrogen peroxide and carbamide peroxide. All trials were however short term and the majority of the studies were judged to be at high risk of bias and were either sponsored or conducted by the manufacturers. There is a need for pragmatic long-term and independent clinical studies that include participants representing diverse populations. There is also a need to evaluate long-term harms. Several studies reported (where measured) the common side effects of tooth sensitivity and gingival irritation, and people should be informed of this.

Adult↗
PubMed2004

The effectiveness of manual versus powered toothbrushes for dental health: a systematic review.

OBJECTIVES: To compare manual and powered toothbrushes in everyday use, principally in relation to plaque removal and gingival health. Stain, calculus removal, dependability, adverse effects and cost were also considered. METHOD: A systematic review was undertaken in collaboration with the Cochrane Oral Health Group. Five electronic databases were searched to identify randomised controlled trials comparing powered and manual toothbrushes. Trials of less than 28 days duration, or where toothbrushing was supervised, were excluded. Assessment of relevance, data extraction and validity assessment were all undertaken independently and in duplicate by two reviewers. Included studies were grouped according to the mode of action of the powered toothbrush. The primary outcomes were plaque and gingival health with data defined as either short-term (1-3 months) or long-term (greater than 3 months) duration were analysed. Powered brushes were categorised into six groups depending on mode of action. Numerical data extracted were checked by a third reviewer for accuracy and entered into RevMan (version 4.1). RESULTS: The initial search identified 354 studies. Two hundred and fifteen full articles were obtained of which 29 trials fulfilled the inclusion criteria with results, which could be entered in the meta-analysis. Twenty-six trials (1786 participants) reported short-term and 10 trials (798 participants) long-term plaque scores. Twenty-nine trials (2236 participants) reported short-term and 10 trials (798 participants) long-term gingivitis scores. Powered brushes reduced plaque and gingivitis at least as effectively as manual brushing. Rotation oscillation powered brushes statistically significantly reduced plaque and gingivitis in both the short and long-term. For plaque at one to 3 months the standardised mean difference was -0.44 (95% CI: -0.66 to -0.21), for gingivitis SMD -0.45 (95% CI: -0.76, -0.15). These represented an 11% reduction on the Quigley Hein Plaque index and a 6% reduction on the Löe and Silness gingival index. At over 3 months the effects were SMD for plaque -1.15 (95% CI: -2.02, -0.29) and SMD for gingivitis -0.51 (95% CI: -0.76, -0.25). These represented a 7% reduction on the Quigley Hein Plaque Index and a 17% reduction on the Ainamo Bay Bleeding on Probing Gingival Index. Sensitivity analyses revealed the results to be robust when selecting trials of high quality. There was no evidence of any publication bias. No other powered brush designs were consistently superior to manual toothbrushes. In these trials, data on cost, reliability and side effects were inconsistently reported. CONCLUSION: In general there was no evidence of a statistically significant difference between powered and manual brushes. However, rotation oscillation powered brushes significantly reduce plaque and gingivitis in both the short and long-term. The clinical significance of this reduction is not known. Observation of methodological guidelines and greater standardisation of design would benefit both future trials and meta-analyses.

Dental Devices, Home Care↗
PubMed2005

Systemic administration of local anesthetic agents to relieve neuropathic pain.

BACKGROUND: Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described the use of intravenous lidocaine or procaine to relieve cancer and postoperative pain (Keats 1951; Gilbert 1951; De Clive-Lowe 1958; Bartlett 1961). Interest reappeared decades later when patient series and clinical trials reported that parenteral lidocaine and its oral analogs tocainide, mexiletine, and flecainide relieved neuropathic pain in some patients (Boas 1982; Lindblom 1984; Petersen 1986; Dunlop 1988; Bach 1990; Awerbuch 1990). With the recent publication of clinical trials with high quality standards, we have reviewed the use of systemic lidocaine and its oral analogs in neuropathic pain to update our knowledge, to measure their benefit and harm, and to better define their role in therapy. OBJECTIVES: To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions. SEARCH STRATEGY: We searched MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through 15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter, 2004), System for Information on Grey Literature in Europe (SIGLE), and LILACS, from January 1966 through March 2001. We also hand searched conference proceedings, textbooks, original articles and reviews. SELECTION CRITERIA: We included trials with random allocation, that were double blinded, with a parallel or crossover design. The control intervention was a placebo or an analgesic drug for neuropathic pain from any cause. DATA COLLECTION AND ANALYSIS: We collected efficacy and safety data from all published and unpublished trials. We calculated combined effect sizes using continuous and binary data for pain relief and adverse effects as primary and secondary outcome measurements, respectively. MAIN RESULTS: Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI: -15 to -7; P <0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias. AUTHORS' CONCLUSIONS: Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful. NOTES: Notes 2017 A restricted search in June 2017 did not identify any potentially relevant studies likely to change the conclusions. Therefore, this review has now been stabilised following discussion with the authors and editors. If appropriate, we will update the review if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions. 2019 We performed another restricted search in September 2019 but did not identify any potentially relevant studies likely to change the conclusions. Therefore, this review has now been stabilised following discussion with the authors and editors, and we will reassess the review for updating in 2020. If appropriate, we will update the review sooner if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions. 2020 We performed another restricted search in September 2020 but again did not identify any potentially relevant studies likely to change the conclusions. This area of research is not active and therefore this review has now been stabilised following discussion with the authors and editors; we will reassess the review for updating in 2025. If appropriate, we will update the review sooner if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions.

Administration, Oral↗
PubMedDate not supplied

Safety assessment of biotechnology-derived pharmaceuticals: ICH and beyond.

Many scientific discussions, especially in the past 8 yr, have focused on definition of criteria for the optimal assessment of the preclinical toxicity of pharmaceuticals. With the current overlap of responsibility among centers within the Food and Drug Administration (FDA), uniformity of testing standards, when appropriate, would be desirable. These discussions have extended beyond the boundaries of the FDA and have culminated in the acceptance of formalized, internationally recognized guidances. The work of the International Committee on Harmonisation (ICH) and the initiatives developed by the FDA are important because they (a) represent a consensus scientific opinion, (b) promote consistency, (c) improve the quality of the studies performed, (d) assist the public sector in determining what may be generally acceptable to prepare product development plans, and (e) provide guidance for the sponsors in the design of preclinical toxicity studies. Disadvantages associated with such initiatives include (a) the establishment of a historical database that is difficult to relinquish, (b) the promotion of a check-the-box approach, i.e., a tendancy to perform only the minimum evaluation required by the guidelines, (c) the creation of a disincentive for industry to develop and validate new models, and (d) the creation of state-of-the-art guidances that may not allow for appropriate evaluation of novel therapies. The introduction of biotechnology-derived pharmaceuticals for clinical use has often required the application of unique approaches to assessing their safety in preclinical studies. There is much diversity among these products, which include the gene and cellular therapies, monoclonal antibodies, human-derived recombinant regulatory proteins, blood products, and vaccines. For many of the biological therapies, there will be unique product issues that may require specific modifications to protocol design and may raise additional safety concerns (e.g., immunogenicity). Guidances concerning the design of preclinical studies for such therapies are generally based on the clinical indication. Risk versus benefit decisions are made with an understanding of the nature of the patient population, the severity of disease, and the availability of alternative therapies. Key components of protocol design for preclinical studies addressing the risks of these agents include (a) a safe starting dose in humans, (b) identification of potential target organs, (c) identification of clinical parameters that should be monitored in humans, and (d) identification of at-risk populations. One of the distinct aspects of the safety evaluation of biotechnology-derived pharmaceuticals is the use of relevant and often nontraditional species and the use of animal models of disease in preclinical safety evaluation. Extensive contributions were made by the Center for Biologics Evaluation and Research to the ICH document on the safety of biotherapeutics, which is intended to provide worldwide guidance for a framework approach to the design and review of preclinical programs. Rational, scientifically sound study design and early identification of the potential safety concerns that may be anticipated in the clinical trial can result in preclinical data that facilitate use of these novel therapies for use in humans without duplication of effort or the unnecessary use of animals.

Animals↗
PubMed2005

Fluoridated milk for preventing dental caries.

BACKGROUND: Dental caries remains a major public health problem in most industrialised countries, affecting 60% to 90% of school children and the vast majority of adults. Milk provides a relatively cost-effective vehicle for fluoride in the prevention of dental caries. OBJECTIVES: To determine the effectiveness of fluoridated milk, as a means of delivering fluoride on a community basis, for preventing dental caries. SEARCH STRATEGY: We searched Cochrane Oral Health Group Trials Register (28 April 2005), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2005), MEDLINE (1966 to 17 May 2005), OLDMEDLINE (1950 to 1965), EMBASE (1980 to 2005 week 20), LILACS (1982 to 17 May 2005), BBO (1986 to 17 May 2005), SIGLE (1980 to 17 May2005), Digital Dissertations (1861 to 17 May 2005) and reference lists of relevant articles. Attempts were made to identify both unpublished and ongoing studies. There were no language restrictions. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials (RCTs), with an intervention or follow-up period of at least 3 years, comparing fluoridated milk with non-fluoridated milk. Primary outcome was change in caries experience, as measured by changes in decayed, missing and filled figures on tooth (dmft/DMFT) and surface (dmfs/DMFS). DATA COLLECTION AND ANALYSIS: Inclusion decisions, data extraction and quality assessment were carried out independently and in duplicate. Study authors were contacted for additional information where necessary. MAIN RESULTS: Two RCTs involving 353 children were included. For permanent teeth, after 3 years there was a significant reduction in the DMFT (78.4%, P < 0.05) between the test and control groups in one trial, but not in the other. The latter study only showed a significant reduction in the DMFT until the fourth (35.5%, P < 0.02) and fifth (31.2%,P < 0.05) years. For primary teeth, again there was a significant reduction in the dmft (31.3%, P< 0.05) between the test and control groups after 3 years in one study, but not in the other. The results could not be pooled because of the difference in concentration of fluoride in the milk. AUTHORS' CONCLUSIONS: There are insufficient studies with good quality evidence examining the effects of fluoridated milk in preventing dental caries. However, the included studies suggested that fluoridated milk was beneficial to school children, especially their permanent dentition. The data need to be supplemented by further RCTs to provide the highest level of evidence for practice.

Animals↗
PubMed2026

Methods for defining equity-stratifying variables: a systematic review of validation studies.

BACKGROUND AND OBJECTIVE: Disease burden is often disproportionally higher among those who are socially disadvantaged by factors defined in the PROGRESS-Plus framework (ie, Place of residence, Race/ethnicity/culture/language, Occupation, Gender/sex, Religion, Education, Socioeconomic status, and Social capital, with "Plus" covering features like age and disability). The accuracy and applicability of case definitions to identify these variables from administrative and clinical health data are unknown. We conducted a systematic review to explore how equity-stratifying variables, as categorized by the PROGRESS-Plus framework, have been defined and validated in epidemiologic studies using administrative health, population-level, or electronic health record (EHR) data. METHODS: Medline, EMBASE, CINAHL, Web of Science, and Google Scholar were searched from the inception of the databases to 2024 for validation studies of equity-stratifying variables in adults using administrative health datasets, health registries, or EHR data. Titles and abstracts, followed by relevant full-text articles, were screened in duplicate by two reviewers for eligibility. The data sources utilized, algorithms employed, and their associated performance measures were extracted and synthesized from included studies. Given substantial heterogeneity in study design, equity-stratifying variable definition, and performance metrics, meta-analysis was not possible. RESULTS: Of the 9099 unique citations screened, 188 full texts were reviewed and 116 were included in this review. Most studies were published between 2019 and 2024 (n = 64, 55%) and were validation studies of race/ethnicity definitions that used race/ethnicity codes or surname list algorithms (n = 66, 57%). No studies examined religion. Regarding the reported performance measure estimates, the race/ethnicity/culture/language equity-stratifying variables category had the largest variability across sensitivity, positive predictive value (PPV), and Cohen's Kappa. Occupation validation studies had the lowest variation in sensitivity and PPV. CONCLUSION: Despite an increasing number of publications reporting on the validation of equity-stratifying variables relevant to the PROGRESS-Plus framework, performance measures varied widely across studies. The significant heterogeneity in equity-stratifying variable definitions and methods used to validate them support the need for further rigorous validation of equity-stratifying variables in administrative and clinical health data. PLAIN LANGUAGE SUMMARY: Disease burden is often higher in people who experience financial hardships, lower level of education, discrimination due to race/ethnicity, and unstable housing. These social factors can be considered health equity factors and are important for understanding health inequalities. Health researchers often use large datasets, such as hospital or electronic health records (EHRs), to study these health equity factors. However, it is not clear how accurately these data sources capture information about people's social circumstances and how these factors are defined. In this study, we reviewed existing research to understand how health equity factors have been defined across health data sources and how accurate they are at measuring aspects of health equity and social disadvantage. Of the more than 9000 studies we identified, we included 116 that met our criteria for this systematic review. Most included studies focused on identifying race and ethnicity, often using codes or surname-based methods. We found that the accuracy of these methods varied widely across studies, meaning results may not always be reliable or comparable. Overall, our findings show that there are inconsistencies in how social factors are defined and measured in health data. This makes it difficult to fully understand and address health inequalities using routinely collected health data. More work is needed to develop and validate better quality and more consistent methods for capturing these important social factors.

Humans↗
PubMed2001

Insulin glargine.

BACKGROUND: In diabetes mellitus, the clinical goal of intensive glycemic control (lowering blood glucose concentrations to normal or near-normal levels) has been hindered by the lack of insulin regimens that duplicate the basal-bolus secretion of insulin by the healthy pancreas. In particular, intensive therapy has been associated with a risk of hypoglycemia. OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, and potential drug interactions of insulin glargine, a new long-acting recombinant human insulin analogue. Results of clinical trials of its efficacy and tolerability as a basal insulin in the treatment of type 1 and type 2 diabetes are summarized. METHODS: Primary research and review articles on insulin glargine were identified through a search of MEDLINE from 1966 to July 2001. Abstracts were identified through a search of the Institute for Scientific Information Web of Science from 1995 to July 2001 and proceedings of American Diabetes Association scientific meetings. Additional information was obtained from the product information for insulin glargine. All identified articles and abstracts were evaluated for relevance, and all relevant information was included in the review. Priority was given to data from the primary medical literature. RESULTS: Insulin glargine has a slower onset of action than human neutral protamine Hagedorn (NPH) insulin, a longer duration of action (up to 24 hours), and no pronounced peak. It has similar tolerability and produces similar glycemic control to once- or twice-daily human NPH insulin, with a similar glucose-lowering effect on a molar basis. A decreased incidence of hypoglycemia, particularly at night, has been reported with insulin glargine compared with human NPH insulin. Insulin glargine appears to be comparable to human NPH insulin in terms of toxicity, adverse effects, immunogenicity, and potential for drug interactions. Results of clinical trials of insulin glargine in both type 1 and type 2 diabetes support its use in combination with a short-acting insulin, insulin lispro, or oral antidiabetic medications. Although insulin glargine cannot be mixed with other insulin preparations, it has the potential convenience of providing basal insulin with once-daily bedtime dosing. CONCLUSIONS: Based on the as yet small amount of data from full clinical study reports in peer-reviewed publications, insulin glargine appears to be a well-tolerated and effective basal insulin preparation for patients with type 1 or type 2 diabetes (including pediatric patients). Its delayed onset of action and prolonged, flat time-action profile mimic the action of endogenous basal insulin (or an insulin pump), decreasing the risk of hypoglycemic episodes. Insulin glargine may be a useful new option for meeting overnight insulin requirements, although most patients will require a rapid-acting insulin such as insulin lispro with or before meals for optimal management of blood glucose levels.

Adult↗
PubMed2005

Intraarticular corticosteroid for treatment of osteoarthritis of the knee.

BACKGROUND: Osteoarthritis (OA) is a common joint disorder. In the knee, injections of corticosteroids into the joint (intra-articular (IA)) may relieve inflammation, and reduce pain and disability. OBJECTIVES: To evaluate the efficacy and safety of IA corticosteroids in treatment of OA of the knee. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE, EMBASE, PREMEDLINE (all to July 2003), and Current Contents (Sept 2000). Specialised journals, trial reference lists and review articles were handsearched. SELECTION CRITERIA: Randomised controlled trials of IA corticosteroids for patients with OA of the knee: single/double blind, placebo-based/comparative studies, reporting at least one core OMERACT III outcome measure. DATA COLLECTION AND ANALYSIS: Methodological quality of trials was assessed, and data were extracted in duplicate. Fixed effect and random effects models, giving weighted mean differences (WMD), were used for continuous variables. Dichotomous outcomes were analysed by relative risk (RR). MAIN RESULTS: Twenty-six trials (1721 participants) comparing IA corticosteroid against placebo, against IA hyaluronan/hylan (HA products), against joint lavage, and against other IA corticosteroids, were included.IA corticosteroid was more effective than IA placebo for pain reduction (WMD -17.79; 95% confidence interval (CI) -25.02 to -10.55) and patient global assessment (the RR was 1.44 (95% CI 1.13 to 1.82)) at one week post injection with an NNT of 3 to 4 for both, based on n=185 for pain on 100 mm visual analogue scale (VAS) and n=158 for patient global assessment. Data on function were sparse at one week post injection and neither statistically significant nor clinically important differences were detected. There was evidence of pain reduction between two weeks (the RR was 1.81 (95% CI 1.09 to 3.00)) to three weeks (the RR was 3.11 (95% CI 1.61 to 6.01), but a lack of evidence for efficacy in functional improvement. At four to 24 weeks post injection, there was lack of evidence of effect on pain and function (small studies showed benefits which did not reach statistical or clinical importance, i.e. less than 20% risk difference). For patient global, there were three studies which consistently showed lack of effect longer than one week post injection. However, all were fairly small sample sizes (less than 50 patients per group). This was supported by another study which did not find statistically significant differences, at any time point, on a continuous measure of patient global assessment (100 mm VAS). In comparisons of corticosteroids and HA products, no statistically significant differences were in general detected at one to four weeks post injection. Between five and 13 weeks post injection, HA products were more effective than corticosteroids for one or more of the following variables: WOMAC OA Index, Lequesne Index, pain, range of motion (flexion), and number of responders. One study showed a difference in function between 14 to 26 weeks, but no differences in efficacy were detected at 45 to 52 weeks. In general, the onset of effect was similar with IA corticosteroids, but was less durable than with HA products. Comparisons of IA corticosteroids showed triamcinolone hexacetonide was superior to betamethasone for number of patients reporting pain reduction up to four weeks post injection (the RR was 2.00 (95% CI 1.10 to 3.63). Comparisons between IA corticosteroid and joint lavage showed no differences in any of the efficacy or safety outcome measures. AUTHORS' CONCLUSIONS: The short-term benefit of IA corticosteroids in treatment of knee OA is well established, and few side effects have been reported. Longer term benefits have not been confirmed based on the RevMan analysis. The response to HA products appears more durable. In this review, some discrepancies were observed between the RevMan 4.1 analysis and the original publication. These are likely the result of using secondary rather than primary data and the statistical methods available in RevMan 4.1. Future trials should have standardised outcome measures and assessment times, run longer, investigate different patient subgroups, and clinical predictors of response (those associated with inflammation and structural damage).

Adrenal Cortex Hormones↗
PubMed2006

Intraarticular corticosteroid for treatment of osteoarthritis of the knee.

BACKGROUND: Osteoarthritis (OA) is a common joint disorder. In the knee, injections of corticosteroids into the joint (intraarticular (IA)) may relieve inflammation, and reduce pain and disability. OBJECTIVES: To evaluate the efficacy and safety of IA corticosteroids in treatment of OA of the knee. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE (to January (week 1) 2006 for update), EMBASE, PREMEDLINE (all to July 2003), and Current Contents (Sept 2000). Specialised journals, trial reference lists and review articles were handsearched. SELECTION CRITERIA: Randomised controlled trials of IA corticosteroids for patients with OA of the knee: single/double blind, placebo-based/comparative studies, reporting at least one core OMERACT III outcome measure. DATA COLLECTION AND ANALYSIS: Methodological quality of trials was assessed, and data were extracted in duplicate. Fixed effect and random effects models, giving weighted mean differences (WMD), were used for continuous variables. Dichotomous outcomes were analysed by relative risk (RR). MAIN RESULTS: Twenty-eight trials (1973 participants) comparing IA corticosteroid against placebo, against IA hyaluronan/hylan (HA products), against joint lavage, and against other IA corticosteroids, were included.IA corticosteroid was more effective than IA placebo for pain reduction (WMD -21.91; 95% confidence interval (CI) -29.93 to -13.89) and patient global assessment (the RR was 1.44 (95% CI 1.13 to 1.82)) at one week post injection with an NNT of 3 to 4 for both, based on n=185 for pain on 100 mm visual analogue scale (VAS) and n=158 for patient global assessment. Data on function were sparse at one week post injection and neither statistically significant nor clinically important differences were detected. There was evidence of pain reduction between two weeks (the RR was 1.81 (95% CI 1.09 to 3.00)) to three weeks (the RR was 3.11 (95% CI 1.61 to 6.01), but a lack of evidence for efficacy in functional improvement. At four to 24 weeks post injection, there was lack of evidence of effect on pain and function (small studies showed benefits which did not reach statistical or clinical importance, i.e. less than 20% risk difference). For patient global, there were three studies which consistently showed lack of effect longer than one week post injection. However, all were fairly small sample sizes (less than 50 patients per group). This was supported by another study which did not find statistically significant differences, at any time point, on a continuous measure of patient global assessment (100 mm VAS).In comparisons of corticosteroids and HA products, no statistically significant differences were in general detected at one to four weeks post injection. Between five and 13 weeks post injection, HA products were more effective than corticosteroids for one or more of the following variables: WOMAC OA Index, Lequesne Index, pain, range of motion (flexion), and number of responders. One study showed a difference in function between 14 to 26 weeks, but no differences in efficacy were detected at 45 to 52 weeks. In general, the onset of effect was similar with IA corticosteroids, but was less durable than with HA products. Comparisons of IA corticosteroids showed triamcinolone hexacetonide was superior to betamethasone for number of patients reporting pain reduction up to four weeks post injection (the RR was 2.00 (95% CI 1.10 to 3.63). Comparisons between IA corticosteroid and joint lavage showed no differences in any of the efficacy or safety outcome measures. AUTHORS' CONCLUSIONS: The short-term benefit of IA corticosteroids in treatment of knee OA is well established, and few side effects have been reported. Longer term benefits have not been confirmed based on the RevMan analysis. The response to HA products appears more durable. In this review, some discrepancies were observed between the RevMan 4.2 analysis and the original publication. These are likely the result of using secondary rather than primary data and the statistical methods available in RevMan 4.2. Future trials should have standardised outcome measures and assessment times, run longer, investigate different patient subgroups, and clinical predictors of response (those associated with inflammation and structural damage).

Adrenal Cortex Hormones↗
PubMed2000

Acupuncture for smoking cessation.

BACKGROUND: Acupuncture is promoted as a treatment for smoking cessation, and is believed to reduce withdrawal symptoms. OBJECTIVES: The objective of this review is to determine the effectiveness of acupuncture in smoking cessation in comparison with: a) sham acupuncture b) other interventions c) no intervention. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register, Medline, PsycLit, Dissertation Abstracts, Health Planning and Administration, Social SciSearch, Smoking & Health, Embase, Biological Abstracts and DRUG. SELECTION CRITERIA: Randomised trials comparing a form of acupuncture with either sham acupuncture, another intervention or no intervention for smoking cessation. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of subjects, the nature of the acupuncture and control procedures, the outcome measures, method of randomisation, and completeness of follow-up. We assessed abstinence from smoking at the earliest time-point (before 6 weeks), at six months and at one year follow-up in patients smoking at baseline. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Those lost to follow-up were counted as continuing to smoke. Where appropriate, we performed meta-analysis using a fixed effects model. MAIN RESULTS: We identified 18 publications involving 20 comparisons. Acupuncture was not superior to sham acupuncture in smoking cessation at any time point. The odds ratio (OR) for early outcomes was 1.22 (95% confidence interval 0.99 to 1.49); the OR after 6 months was 1.38 (95% confidence interval 0.90 to 2.11) and after 12 months 1.02 (95% confidence interval 0.72 to 1.43). Similarly, when acupuncture was compared with other anti-smoking interventions, there were no differences in outcome at any time point. Acupuncture appeared to be superior to no intervention in the early results, but this difference was not sustained. The results with different acupuncture techniques do not show any one particular method (i.e. auricular acupuncture or non-auricular acupuncture) to be superior to control intervention. REVIEWER'S CONCLUSIONS: There is no clear evidence that acupuncture is effective for smoking cessation.

Acupuncture Therapy↗
PubMed2002

Interventions for replacing missing teeth: different types of dental implants.

BACKGROUND: Dental implants are available in different materials, shapes and with different surface characteristics. In particular, numerous implant surface modifications have been developed for enhancing clinical performances. OBJECTIVES: To test the null hypothesis of no difference in clinical performance between various root-formed osseointegrated implant types. SEARCH STRATEGY: The Cochrane Oral Health Group Specialised Trials Register, The Cochrane Controlled Trials Register, MEDLINE and EMBASE were searched. Hand searching included several dental journals. Bibliographies of relevant clinical trials and review articles were checked for studies outside the handsearched journals. In addition, authors of all identified trials and fifty-five oral implant manufacturers were contacted to find unpublished or ongoing RCTs. Two extensive personal libraries (ME and AJ) were consulted. The last electronic search was conducted 8th May 2002. SELECTION CRITERIA: All randomised controlled trials of oral implants comparing implants with different materials, shapes and surface properties having a follow-up of at least one year. DATA COLLECTION AND ANALYSIS: Data were independently extracted, in duplicate, by two reviewers (ME & HW). Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The Cochrane Oral Health Group's statistical guidelines were followed. MAIN RESULTS: Thirty publications, representing 13 different RCTs, were identified. Five of these RCTs (seven publications), which reported results from a total of 326 patients, were suitable for inclusion in the review. Six implant systems were compared: Astra, Branemark, IMZ, ITI, Steri-Oss and Southern with a follow-up ranging from one to three years. All implants were made in commercially pure titanium and had different shapes and surface preparations. On a patient rather than per implant basis there were no statistically significant differences for failures and marginal bone level changes on intra-oral radiographs between various implant systems. REVIEWER'S CONCLUSIONS: There was no evidence that any of the implant systems evaluated was superior to the other. However, these findings are based on a few RCTs all having short follow-up periods and few participants. More RCTs should be conducted, with follow-up of at least five years and including a sufficient number of patients, to detect a true difference if any exists. Such trials should be reported according to the CONSORT guidelines (http://www.consort-statement.org/).

Dental Implantation, Endosseous↗
PubMed2003

Combined hormonal versus nonhormonal versus progestin-only contraception in lactation.

BACKGROUND: Contraception for women who are breastfeeding is a public health issue of global importance. Each year over 100 million women make decisions about beginning or resuming contraception after childbirth. These decisions include both the choice of contraceptive method and the time at which its use begins, both of which continue to be debated by experts. Choices of contraception may be limited for lactating women due to concerns about hormonal effects on quality and quantity of milk, passage of hormones to the infant, and infant growth. Ideally, the contraceptive method chosen should not interfere with lactation. Additionally, because the return of menstruation and ovulation can be unpredictable in breastfeeding women, the timing of contraception initiation is important. OBJECTIVES: To determine the effect of combined oral contraceptives and progestin-only contraceptives on lactation. The a priori hypothesis is that combined oral contraception impairs lactation, making it less appropriate than progestin-only or nonhormonal contraception for breastfeeding women. SEARCH STRATEGY: We used PUBMED, POPLINE, EMBASE, LILACS, and Cochrane Controlled Trials Register computer searches, supplemented by review articles and contact with investigators. SELECTION CRITERIA: We sought all randomized controlled trials, reported in any language, that included any form of hormonal contraception compared with another form of hormonal contraception, nonhormonal contraception, or placebo during lactation. Hormonal contraception could include combined oral or injectable contraceptives, progestin-only oral or injectable contraceptives, hormonal implants, or hormonal intrauterine devices. Study participants included breastfeeding women of any age or parity who desired contraception. DATA COLLECTION AND ANALYSIS: We evaluated the methodological quality of each report and sought to identify duplicate reporting of data from multicenter trials. We abstracted data onto data collection forms. Principal outcome measures included quantity of milk; biochemical analysis of milk composition; initiation, maintenance and duration of lactation; infant growth; efficacy of contraceptive method while breastfeeding; and timing of contraception initiation and its effects on lactation. Because the trials did not have uniform interventions, often lacked quantifiable outcomes, and had poor methodological quality, we could not aggregate the data in a meta-analyses. MAIN RESULTS: Seven reports from five randomized controlled trials met our inclusion criteria. Most of the five trials did not specify their method used to generate a random sequence, method of allocation concealment, blinding of treatments, or use of an intention-to-treat analysis. Additionally, high loss to follow-up rates invalidated at least two studies. The findings from two reports comparing oral contraceptives to placebo during lactation were conflicting. Another trial found no inhibitory effects on lactation from progestin-only contraceptives. Finally, the WHO trial found no effect of progestin-only contraceptives on lactation but a decline in breast milk volume from combination contraceptives during lactation. High loss to follow-up rates, however, undermine the credibility of the WHO trial. No significant differences in infant growth or weight appeared in any of the included trials as a result of the use of hormonal contraception during lactation. REVIEWER'S CONCLUSIONS: Evidence from randomized controlled trials on the effect of hormonal contraceptives during lactation is limited and of poor quality; results should be interpreted with caution. The existing randomized controlled trials are insufficient to establish an effect of hormonal contraception, if any, on milk quality and quantity. Evidence is inadequate to make recommendations regarding hormonal contraceptive use for lactating women. At least one properly conducted randomized controlled trial of adequate size is urgently needed to address this question.

Contraceptives, Oral, Combined↗