bluuebunny/crossref_metadata_2025 huggingface dataset:
BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways
Authors: Yoon Byeong S. , Pogue Robert , Ovchinnikov Dmitri A. , Yoshii Isaac , Mishina Yuji , Behringer Richard R. , Lyons Karen M.
Published: October 2006

Bone morphogenetic protein (BMP) signaling pathways are essential regulators of chondrogenesis. However, the roles of these pathways in vivo are not well understood. Limb-culture studies have provided a number of essential insights, including the demonstration that BMP pathways are required for chondrocyte proliferation and differentiation. However, limb-culture studies have yielded contradictory results; some studies indicate that BMPs exert stimulatory effects on differentiation, whereas others support inhibitory effects. Therefore, we characterized the skeletal phenotypes of mice lacking Bmpr1a in chondrocytes (Bmpr1aCKO) and Bmpr1aCKO;Bmpr1b+/-(Bmpr1aCKO;1b+/-) in order to test the roles of BMP pathways in the growth plate in vivo. These mice reveal requirements for BMP signaling in multiple aspects of chondrogenesis. They also demonstrate that the balance between signaling outputs from BMP and fibroblast growth factor (FGF) pathways plays a crucial role in the growth plate. These studies indicate that BMP signaling is required to promote Ihh expression,and to inhibit activation of STAT and ERK1/2 MAPK, key effectors of FGF signaling. BMP pathways inhibit FGF signaling, at least in part, by inhibiting the expression of FGFR1. These results provide a genetic in vivo demonstration that the progression of chondrocytes through the growth plate is controlled by antagonistic BMP and FGF signaling pathways.
Ossifying fibroma of the head and neck: Involvement of the temporal bone — an unusual and challenging site
Authors: Levine Paul A. , Wiggins Robert , Archibald Robert W. R. , Britt Richard
Published: October 2006

Ossifying fibroma of the head and neck is most commonly described in the mandible and maxilla. A few isolated reports in the literature exhibit the rare existence of this lesion in the nasal bones, orbit, ethmoid sinus, sphenoid sinus, occiput, and in only two well‐documented cases, the temporal bone. We present the case of an extensive ossifying fibroma of the temporal bone that presented as a suspected case of hypertosis of the external auditory canal and conductive hearing loss, without any cosmetic deformity. A review of the recent literature concerning the sites, radiologic presentation, difficulty of pathologic differentiation, and modality of therapy is discussed.
Avulsion of the upper lateral cartilage: Etiology, diagnosis, surgical anatomy and management
Authors: Parkes Morey L. , Kanodia Raj
Published: October 2006

Relatively little has been published about upper lateral cartilage abnormalities, trauma, and management in rhinoplastic literature. In this paper we would like to present a relatively common problem seen either by trauma or as a result of rhinoplasty.

The upper lateral cartilages are a pair of triangular cartilages, one on each side of the dorsum, which comprise the upper cartilaginous vault with the septum and can be avulsed due to direct trauma. This results in loss of their attachments and resultant healing in a new angulated position. The middle third of the nose, being relatively mobile, is less susceptible to trauma than the upper third which is rigid and comprised of bone, and that frequently is the reason for less incidence of avulsion of the upper lateral cartilages compared to fractured nasal bones. The surgical treatment of the structures adjacent to the upper lateral cartilage during the process of rhinoplasty severs many attachments of these cartilages and frequently causes them to be free floating. This may not be recognized and not treated. Lack of appropriate realignment in the normal anatomical position may heal the cartilage in a distorted angulated position. Irrespective of etiology, when distortions of the upper lateral cartilage occur, they may cause significant concavity and “hollowed out” appearance on the side of the avulsion which functionally may impede the nasal airway by encroachment and/or “flutter valve” effect. During inspiration this unsupported upper lateral cartilage may interfere with anatomy, physiology and efficiency of the internal nasal valve function.

Avulsion of the upper lateral cartilage is a definite entity and should be recognized and treated appropriately to realign the lateral cartilage in its normal anatomical position for a functional as well as a good cosmetic result.
Surgery on the only hearing ear
Authors: Althaus Sean R.
Published: October 2006

Modern otosurgical tools and techniques have greatly improved the outlook for hearing improvement in otologic surgery, while decreasing the risk of severe and irreversible hearing loss complicating the surgical procedure. Nevertheless, even a minimal risk operation must be weighed differently in an only hearing ear situation.

This paper reviews the author's experience and philosophy regarding only hearing ear surgery for chronic otitis media, endolymphatic hydrops, perilymph fistulas and acoustic neuromas.
Bilateral primary malignant neoplasms of the maxillary sinus: Report of a case and statistical analysis of the reports in japan
Authors: Ichimura Keiichi , Nozue Michihiko , Hoshino Tomoyuki , Yano Jun
Published: October 2006

Although double primary malignant neoplasms of bilateral maxillary sinuses were regarded as extremely rare, there have been 50 patients described in Japan since 1937. Among them only eight cases showed the histologic distinction between both sides.

A 64‐year‐old man with double primary carcinomas had a mucoepidermoid carcinoma of the left maxillary sinus and a papillary adenocarcinoma of the right one with an interval of three years. He was treated with a combination of surgery, radiotherapy and regional chemotherapy. The histologic combination of these tumors could not be found so far. The advantage of this combination treatment for the carcinoma of the maxillary sinus is stressed.
Neck dissection: Is it worthwhile?
Authors: Desanto Lawrence W. , Holt James J. , Beahrs Oliver H. , O'Fallon W. Michael
Published: October 2006

Data on 1,048 neck dissections in 881 patients were studied to evaluate the effectiveness of treatment in controlling cervical metastasis. Of the 881 patients, 74.5% were treated by surgery alone, and most of the reMaynder had either planned preoperative or postoperative radiation to the primary site and the entire neck. Planned preoperative or postoperative radiation was defined as the delivery of 4,000 rads or more to the entire neck 123 days before (preoperative) or after (postoperative) neck dissection. In these groups, most patients received more than 5,000 rads. Ninety‐six patients received preoperative radiation that did not satisfy these criteria and were grouped separately. The group with neck dissection alone had recurrence rates in the dissected side at 2 years of 7.5, 20.2, and 37.4%, respectively, for No, N1, and N2 staged necks. There were no differences in recurrence rates for the groups with radiated necks in the stage II (N2) necks compared with each other or with the group having surgery alone. Most recurrences, when they occurred in the neck, were manifest by 2 years. Mean follow‐up in the entire study was 3.5 years. Two patients were lost to follow‐up and were presumed to have died from cancer. When compared with pathologic staging, clinical staging was imprecise in one‐third of the cases.
A specimen mount for small laryngeal biopsies
Authors: Holinger Lauren D. , Miller Iii Alexander W.
Published: October 2006

Accurate histologic interpretation of small laryngeal biopsies is often obfuscated by tangential sectioning of the specimen. The natural tendency of the tissue specimen to curl and suboptimnl orientation of the specimen account for the tangential cuts. Use of a biopsy specimen mount eliminates this problem. The biopsy specimen mount also permits accurate determination of tumor involvement of deep and peripheral margins, a useful feature in the management of small areas of leukoplakia of the vocal cords. The biopsy specimen mount is therefore helpful in the endoscopic surgical management of early glottic malignancy (T1s, T1), since therapy can be individualized and planned rationally with precise determination of margin involvement.
Occupational hearing loss: An ontario perspective
Authors: Alberti P. W. , Blair R. L.
Published: October 2006

In the past 11 years over 6,500 patients referred by the Workmen's Compensation Board for evaluation of hearing loss of possible industrial etiology have been evaluated at Mount Sinai Hospital. Various groups of workers have been studied from the audiological, otological, and epidemiological standpoint. Problems of assessment include the accurate quantification of hearing loss which may be difficult for a number of reasons including lack of understanding of the test and lack of willingness to cooperate. An accurate diagnosis may be difficult to achieve because of lack of previous history, poor memory, etc. The method of use in Ontario for quantifying hearing loss will be reviewed and its relationship to handicap discussed. The success of rehabilitation by means of hearing aid use will be analyzed. This is surprisingly good.
Computerized tomography of the temporal bone
Authors: Valvassori Galdino E. , Mafee Mahmood F. , Dobben Glen D.
Published: October 2006

Computerized tomography is acquiring an increasingly important role in the radiographic assessment of the temporal bone. In the latest generation of CT scanners, spacial resolution has been reduced to 0.1 cu mm and slice thickness to 1.5 mm.

The Mayn advantages of computerized tomography in comparison to multidirectional tomography are the improved contrast of the images and above all the clear demonstration of soft tissue structures and masses within or adjacent to the temporal bone.

The following three applications of computerized tomography will be discussed

Evaluation of intratemporal soft tissue masses. Computerized tomography allows differentiation of fluid filled from solid masses and vascular tumors.

Assessment of lesions extending outside the temporal bone or into the temporal bone from adjacent structures. In these cases CT will demonstrate the temporal bone involvement and the presence and extension of the intra or extra cranial component of the lesion.

Study of the cerebellopontine angle. Computerized tomography with infusion and combined with pneumocisternography comprise the procedure of choice for the diagnosis of acoustic neuromas and other lesions occurring in this area.
Speech development in aphonic children
Authors: Tucker Harvey M. , Rusnov Melinda , Cohen Lindy
Published: October 2006

It has been well established that pre‐lingually hearing‐impaired children experience difficulties in speech development. Little appears in the literature, however, about speech development in aphonic children. The authors have had the opportunity to manage several children who, for various reasons, were unable to phonate from a pre‐lingual age to approximately the age of 5 or 6 years. The children in this report developed various compensatory means of communication, including unusual laryngeal, non‐laryngeal and nonverbal communication. Representative cases are reviewed and observations are made regarding the effects of aphonia on speech development.
Hypopharyngeal perforation: A complication of endotracheal intubation
Authors: Myers Ernest M.
Published: October 2006

A case of hypopharyngeal perforation secondary to traumatic endotracheal intubation is described. Clinical presentation and surgical treatment are discussed. Early diagnosis is emphasized. Tracheotomy, laryngoscopy and prompt neck exploration are advocated.
Composite autograft for tympanoplasty and tympanomastoid surgery
Authors: Adkins Warren Y.
Published: October 2006

In 1982, 40 composite cartilage perichondrial autografts performed to prevent recurrent cholesteatoma secondary to canal wall defects were reviewed. A follow‐up of those cases, plus 62 new cases, as well as the composite autografts for severe tympanic membrane retractions (55 cases) and selected tympanoplasties (22 cases) is presented. No recurrent cholesteatomas or retraction pockets developed at the graft sites, with one graft failure in the latter group.
Rhinosurgical experience with the transseptal‐transsphenoidal hypophysectomy: Technique and long‐term results
Authors: Gammert Christian
Published: October 2006

Many modifications of extracranial transsphenoidal hy‐pophysectomy exist, but knowledge of the rhinological implications of these procedures is rare. At our institution the transseptal approach is performed as a joint rhinosurgical and neurosurgical procedure. Three hundred nineteen patients were operated on from 1979 to 1984,113 of whom had a rhinological follow‐up for 5 years. Most of the complications were asymptomatic. Thirteen percent of the patients had septal perforations, 3.5% epistaxis, and 36% complained of mild dryness of the nose. An improvement in breathing was noted in 24% of the patients. There was no difference in rhinological complaints between patients who underwent the sublabial approach and those operated via a transnasal approach. Twenty percent of the patients operated on with the sublabial approach had additional temporary complaints in the upper lip; therefore, the transnasal‐transsep‐tal approach is currently our procedure of choice.
Markedly Increased Vitamin B12 Concentrations Attributable to IgG–IgM–Vitamin B12 Immune Complexes
Authors: Bowen Raffick AR , Drake Steven K , Vanjani Rachna , Huey Edward D , Grafman Jordan , Horne McDonald K
Published: October 2006

Background: High serum vitamin B12 concentrations have been reported in patients with hepatic disease, disseminated neoplasia, myeloproliferative disorders, and hypereosinophilic syndromes. We recently discovered an extraordinarily increased vitamin B12 concentration in a patient without these underlying conditions.

Methods: Affinity and size-exclusion chromatography, sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and ELISA methods were used to determine the cause of the increased vitamin B12 concentrations in this patient’s serum.

Results: The protein G column eluates from 2 apparently healthy volunteers and 2 patients with recent vitamin B12 treatment for anemia had vitamin B12 concentrations of <74 pmol/L, whereas the vitamin B12 concentration in the protein G column eluate from the patient was 7380 pmol/L. The elution profile from size-exclusion chromatography of vitamin B12-binding proteins in the patient’s serum revealed an abnormal vitamin-B12-binding protein. SDS–PAGE analysis of the concentrated eluates from the protein G column, under reducing conditions, revealed an additional band with an apparent molecular mass of 76 kDa, which was not present in control column eluates. MALDI-TOF MS identified this band as an IgM heavy chain. By use of a modified ELISA, we determined that the IgM present in the patient’s eluates was associated with the IgG to form IgG-IgM immune complexes.

Conclusions: This case demonstrates the unusual circumstance of a patient with markedly increased vitamin B12 concentrations attributed to immune complexes composed of IgG, IgM, and vitamin B12 and illustrates techniques that can be used to identify this occurrence.
Uniform Application of Copper Sulfate as a Potential Treatment for Controlling Snail Populations in Channel Catfish Production Ponds
Authors: Wise David J , Mischke Charles C , Greenway Terry , Byars Todd S , Mitchell Andrew J
Published: October 2006

A digenetic trematode identified as Bolbophorus sp. has been implicated as a cause of severe mortality and reduced production in commercially raised channel catfish Ictalurus punctatus in the southeastern United States. Currently, chemical control measures to limit the impact of this disease focus on pond shoreline treatments with hydrated lime or copper sulfate to kill the marsh ram's-horn snail Planorbella trivolvis, an intermediate host that inhabits aquatic vegetation around the pond perimeter. Although effective, these treatments have little impact on snails that are not within close proximity to the pond bank. Tests were conducted to determine the feasibility of using elevated levels of copper sulfate pentahydrate (CSP; CuSO4·5H2O), uniformly applied to the surface of the pond water, to eradicate snails from the pond environment. Results demonstrated that uniform application to deliver between 2.5- and 5.0-ppm CSP (0.64–1.27-ppm Cu) was effective in killing snails around the margins of the pond and throughout the water column but may have negatively affected fish health at the high treatment dose. On average, pond treatments killed more than 96% of the test snails, while mortality of the control snails was less than 8.5%. Results of the commercial field trial were similar to those of tests conducted in experimental ponds, where application of CSP at 5.0 ppm was effective in killing snails at all sampling sites. The treatment was also shown to reduce the natural population of snails along the pond margin by 98.3%. These trials indicate that CSP, when uniformly applied to the water, can be used with caution as an effective treatment against the marsh ram's-horn snail in commercial channel catfish production ponds that have chemical characteristics similar to those of tested waters (alkalinity and hardness >200 ppm as CaCO3).
Evaluation of Substrate Type and Density as Factors in Optimizing Growth of Least Chub
Authors: Wagner Eric J , Billman Eric J , Arndt Ronney
Published: October 2006

The least chub Iotichthys phlegethontis is a diminutive and rare cyprinid endemic to the Bonneville Basin of Utah. As part of a species recovery effort, aquaculture techniques were investigated. Three experiments are summarized here: Two compared silt substrate and no substrate, and one evaluated the effect of three different densities on growth and survival. The substrate experiments were an attempt to compare extensive versus intensive culture. In the first test, growth of 4–7-month-old least chub in outdoor aquaria containing 2–3 cm of silt substrate was significantly higher than that of fish in indoor or outdoor aquaria with no substrate. Survival was unaffected by substrate treatment. In another test using fry that had just hatched, mortality rates were significantly higher in the aquaria treatment (mean ± SD = 95.3 ± 2.3%) than in the silt substrate treatment (45.3 ± 23.1%; P = 0.009). Final length was also significantly higher in the simulated ponds (mean ± SD = 10.2 ± 1.2 mm) than in the aquaria with no sediment (6.2 ± 2.7 mm; P < 0.001). In a final, 8-week test, fish rearing densities of 2.27, 11.36, and 22.7 fish/L were compared among 5–6-week-old least chub. Growth and survival were not significantly affected within this range of rearing densities. These results indicate that extensive aquaculture using fertile fry ponds would produce more and faster-growing least chub than intensive raceways or tanks, assuming predation and disease were not factors. High rearing densities are also possible with this schooling species of cyprinid.
Trends in Hyperinsulinemia Among Nondiabetic Adults in the U.S.
Authors: Li Chaoyang , Ford Earl S. , McGuire Lisa C. , Mokdad Ali H. , Little Randie R. , Reaven Gerald M.
Published: October 2006

OBJECTIVE—Insulin resistance and compensatory hyperinsulinemia have been proposed as increasing risk for a variety of abnormalities and clinical syndromes, including type 2 diabetes and cardiovascular disease. Our aim was to assess the trends in the mean concentrations of fasting serum insulin and the prevalence of hyperinsulinemia among nondiabetic adults during the periods of 1988–1994 and 1999–2002 in the U.S.

RESEARCH DESIGN AND METHODS—We conducted analyses of data among men and nonpregnant women without diabetes aged ≥20 years from the Third National Health and Nutrition Examination Survey (NHANES III; 1988–1994; n = 7,926) and NHANES 1999–2002 (n = 2,993). Both surveys were designed to represent the noninstitutionalized civilian U.S. population. We calculated age-adjusted mean concentrations of fasting insulin and the prevalence of hyperinsulinemia defined using the 75th percentile of fasting insulin among nondiabetic individuals as the cutoff value.

RESULTS—The geometric mean concentrations of fasting insulin increased by ∼5% from 1988–1994 to 1999–2002 among nondiabetic adults aged ≥20 years in the U.S. Mexican-American men, men and women aged 20–39 years, and non-Hispanic white women had a greater relative increase in the mean concentrations of fasting insulin than their counterparts. The prevalence of hyperinsulinemia increased by 35.1% overall (38.3% among men and 32.1% among women).

CONCLUSIONS—In parallel with the obesity epidemic, concentrations of fasting insulin and prevalence of hyperinsulinemia have increased remarkably among nondiabetic U.S. adults.
Plasma Retinol-Binding Protein-4 Concentrations Are Elevated in Human Subjects With Impaired Glucose Tolerance and Type 2 Diabetes
Authors: Cho Young Min , Youn Byung-Soo , Lee Hyewon , Lee Namseok , Min Sung-Shik , Kwak Soo Heon , Lee Hong Kyu , Park Kyong Soo
Published: October 2006

OBJECTIVE—The dysregulation of adipokines is closely associated with the pathogenesis of insulin resistance and type 2 diabetes. Retinol-binding protein-4 (RBP4), a new adipokine, was recently reported to provide a link between obesity and insulin resistance. Here, we examined the relation between plasma RBP4 concentrations and various metabolic parameters in humans.

RESEARCH DESIGN AND METHODS—An enzyme-linked immunosorbent assay was developed to measure human RBP4 plasma concentrations, which were then compared with various parameters related to insulin resistance in subjects with normal glucose tolerance (NGT; n = 57), impaired glucose tolerance (IGT; n = 48), and type 2 diabetes (n = 49).

RESULTS—Plasma RBP4 concentrations were higher in the IGT and type 2 diabetic groups than in the NGT group (median 18.9 [range 11.2–45.8], 20.9 [9.9–48.5], and 18.1 μg/ml [9.3–30.5], respectively). However, no difference was found between plasma RBP4 concentrations in the IGT and type 2 diabetic groups. Plasma RBP4 concentrations were found to be associated with sex, waist circumference, fasting plasma glucose, and insulin resistance. Of these, sex and fasting plasma glucose levels were found to be independent determinants of plasma RBP4 concentration.

CONCLUSIONS—Plasma RBP4 concentrations were found to be elevated in subjects with IGT or type 2 diabetes and to be related to various clinical parameters known to be associated with insulin resistance.
Health Care Use and Costs in the Decade After Identification of Type 1 and Type 2 Diabetes
Authors: Johnson Jeffrey A. , Pohar Sheri L. , Majumdar Sumit R.
Published: October 2006

OBJECTIVE—To analyze trends in health care costs in the decade after identification of diabetes, contrasting type 1 and 2 diabetes.

RESEARCH DESIGN AND METHODS—The Canadian National Diabetes Surveillance System criteria were applied to administrative databases to identify incident diabetes cases in 1992. Cases were categorized as type 1 or type 2 diabetes based on patterns of drug use. Per capita health care costs (in 2001 Canadian dollars) for five resource categories were estimated according to the type of diabetes, for the year before identification (1991) and 10 years after (1992–2001) identification of the cases.

RESULTS—We identified 156 type 1 and 3,469 type 2 incident cases of diabetes, from a population base of ∼950,000. The mean (±SD) age of case subjects at index was 61.2 ± 16.7 years, and 54% of subjects were male. Overall annual per capita health expenditures rose considerably in the year after identification of diabetes but then stabilized at a lower level for the next 9 years, ranging from $3,800 to $4,400. From 1992 to 2001, diabetic individuals used $137.1 million in health care resources, most of which (96%) was attributable to type 2 diabetes. The average 10-year cost per individual with diabetes was $37,820 ($33,684 per type 1 and $38,006 per type 2 diabetes case; adjusted P = 0.45).

CONCLUSIONS—Total health expenditures for diabetes are driven by the much larger prevalence of type 2 compared with type 1 diabetes. Policymakers need to acknowledge and allocate resources for diabetes prevention and management accordingly.
Celiac Disease and Risk of Subsequent Type 1 Diabetes
Authors: Ludvigsson Jonas F. , Ludvigsson Johnny , Ekbom Anders , Montgomery Scott M.
Published: October 2006

OBJECTIVE—Earlier studies suggest that children with type 1 diabetes are more likely to have a subsequent diagnosis of celiac disease. However, research is sparse on the risk of subsequent type 1 diabetes in individuals with celiac disease. We sought to determine the risk of subsequent type 1 diabetes diagnosed before the age of 20 years in children and adolescents with celiac disease in a national, general population–based cohort.

RESEARCH DESIGN AND METHODS—We identified 9,243 children with a diagnosis of celiac disease in the Swedish national inpatient register between 1964 and 2003. We then identified five reference individuals matched at time of diagnosis for age, calendar year, sex, and county (n = 45,680). Only individuals with >1 year of follow-up after study entry (diagnosis of celiac disease) were included in the analyses.

RESULTS—Celiac disease was associated with a statistically significantly increased risk of subsequent type 1 diabetes before age 20 years (hazard ratio 2.4 [95% CI 1.9–3.0], P < 0.001). This risk increase was seen regardless of whether celiac disease was first diagnosed between 0 and 2 (2.2 [1.7–2.9], P < 0.001) or 3 and 20 (3.4 [1.9–6.1], P < 0.001) years of age. Individuals with prior celiac disease were also at increased risk of ketoacidosis or diabetic coma before the age of 20 years (2.3 [1.4–3.9], P = 0.001).

CONCLUSIONS—Children with celiac disease are at increased risk of subsequent type 1 diabetes. This risk increase is low considering that 95% of individuals with celiac disease are HLA-DQ2 positive.
Cigarette Smoking Is Associated With Low Glomerular Filtration Rate in Male Patients With Type 2 Diabetes
Authors: De Cosmo Salvatore , Lamacchia Olga , Rauseo Anna , Viti Raffaella , Gesualdo Loreto , Pilotti Alessandra , Trischitta Vincenzo , Cignarelli Mauro
Published: October 2006

OBJECTIVE—The relationship between cigarette smoking and renal dysfunction in diabetes has predominantly been documented in patients with type 1 diabetes. The aim of the present study was to explore the relationship between cigarette smoking and glomerular filtration rate (GFR) in a large cross-sectional study carried out in male subjects with type 2 diabetes. The role of metabolic syndrome in modulating this relationship was also investigated.

RESEARCH DESIGN AND METHODS—One hundred fifty-eight current smokers and 158 never smokers with type 2 diabetes were consecutively recruited. Low GFR was defined as GFR <60 ml/min per 1.73 m2.

RESULTS—The proportion of patients affected by low GFR was significantly higher in current smokers (20.9 vs. 12.0%, P = 0.03). The adjusted risk (odds ratio [OR]) of low GFR in current smokers was 2.20 (95% CI 1.14–4.26, P = 0.02) and markedly higher in patients from the first tertile of disease duration (4.27 [1.26–14.40], P = 0.02). When metabolic syndrome was added to the statistical model exploring the relationship between smoking and low GFR, the risk of low GFR showed a small change, although it did not become any more significant (1.84 [0.98–3.45], P = 0.06). Current smokers showed even higher free oxygen radical test unit values (560.0 ± 91.5 vs. 442.7 ± 87.2, P < 0.0001).

CONCLUSIONS—In a large population of male patients with type 2 diabetes, the risk of low GFR is markedly enhanced by smoking and is at least partially mediated by metabolic syndrome.
The Columbus Program: Building a Community Model of a 21st Century Intelligent Health System
Authors: Leichter Steven B. , Gingrich Newt , Linn Laura , Butler Barbara , Griggs Sheree
Published: October 2006

IN BRIEF

There is widespread and growing interest in modernization of the American health care system. Based in part on initiatives in the Medicare Modernization Act, diabetes has become a focus of initiatives in health care modernization. In this article, the authors describe approaches to health care reform in diabetes leading to an effort to standardize diabetes care according to national guidelines in one city, Columbus, Ga.
Stability Study Designs
Authors: Daphne Lin Tsae‐Yun , Chen Chi Wan
Published: October 2006

A good stability study design is the key to a successful stability program. In this article, stability designs including full, bracketing, and matrixing designs will be exemplified. A full design involves complete testing of all factor combinations at all time points, which can be costly. The pharmaceutical industry would like to apply bracketing or matrixing design so that not every factor combination will be tested at every time point. The statistical aspects of these stability designs will be discussed in relation to the recent Internation Conference on Harmonization (ICH) guidelines. Several commonly used criteria for design comparison will be presented. The statistical and regulatory considerations on the selection of stability design will also be discussed. The stability study should be well designed so the shelf life of the drug product can be estimated with the high degree of accuracy and precision.
Flexible Designs
Authors: Posch Martin , Bauer Peter , Brannath Werner
Published: October 2006

Flexible designs allow for mid‐trial design adaptations in an adaptive interim analysis based on all information collected while controlling the type I error rate. Examples of such adaptations are, for example, sample size reassessment, addition or dropping of interim analysis, or dropping of treatment arms. The crucial feature of the adaptive procedure is that the adaptation rules need not be specified in advance.
Confidence Interval
Authors: Reiczigel Jeno
Published: October 2006

A confidence interval (CI) or interval estimate for an unknown parameter θ is a “from‐to” range calculated from the sample so that it contains θ with a high—usually 90%, 95%, or 99%—probability. CIs can be given for unknown population parameters like the mean, variance, median, proportion, or for model parameters like a regression coefficient, odds ratio, correlation coefficient, or for functions of the above‐mentioned parameters like, for example, the variance/mean ratio, the difference of two proportions or two means, and so on. In clinical studies, CIs are typically given for the mean or median treatment effect, proportion of cure, difference in these outcome measures comparing two treatments, and so on. Practically for anything for which an estimate from the sample is meaningful at all, a CI is also meaningful. For curves like a regression line or a ROC curve, interval estimation results in a so‐called confidence band.
Sample Size Calculation for Comparing Means
Authors: Wang Hansheng , Chow Shein‐Chung
Published: October 2006

In this article, the focus will be on sample size calculation based on a continuous study endpoint for comparing means (i.e., treatment effects) under some study designs. These designs include parallel designs, crossover designs, titration designs, and enrichment designs (2). Among these designs, parallel designs and crossover designs are probably the two mostly commonly used designs.
Sample Size Calculation for Comparing Variabilities
Authors: Wang Hansheng , Chow Shein‐Chung
Published: October 2006

In clinical research, in addition to comparing mean responses between treatment groups, it is also of interest to compare variabilities of responses between treatment groups. In practice, it is a concern that (1) larger variability may result in a worse safety profile and (2) larger variability may decrease the probability of reproducibility of the observed clinical results. Besides, efficacy and safety assessment are often done based on mean responses by assuming that the associated variabilities are the same, which may not be true in many cases. As a result, comparing variabilities of responses between treatment groups has received much attention lately. In order to achieve a desired statistical power when comparing variabilities of responses between treatment groups, commonly used procedures or formulas, which are derived based on comparing mean responses, cannot be applied directly and are necessarily modified.
Analysis of Variance
ANOVA
Authors: Kaufmann Jörg , Schering AG
Published: October 2006

The development of analysis of variance (ANOVA) methodology has in turn had an influenced on the types of experimental research being carried out in many fields. ANOVA is one of the most commonly used statistical techniques, with applications across the full spectrum of experiments in agriculture, biology, chemistry, toxicology, pharmaceutical research, clinical development, psychology, social science, and engineering. The procedure involves the separation of total observed variation in the data into individual components attributable to various factors as well as those caused by random or chance fluctuation. It allows performing hypotheses tests of significance to determine which factors influence the outcome of the experiment. However, although hypothesis testing is certainly a very useful feature of the ANOVA, it is by no means the only aspect. The methodology was originally developed by Sir Ronald A. Fisher, the pioneer and innovator of the use and applications of statistical methods in experimental design who coined the name “Analysis of Variance – ANOVA.”
Categorical Response Models
Authors: Tutz Gerhard
Published: October 2006

This article discusses category response models, with a focus on binary response models with covariates, ordinal responses, and nominal responses. Inferences are provided for multicategorical responses and developments and examples are reviewed.
Diagnostic Studies
Authors: Schwenke Carsten
Published: October 2006

Diagnostic studies are performed to investigate the clinical usefulness of a new diagnostic procedure, for example, a new contrast agent for imaging or a new laboratory test to detect antibodies or antigens in blood. Sometimes, these studies are invented to substitute the standard procedure by an improved or less expensive procedure, which is not inferior in terms of efficacy and has some benefit compared with the standard procedure. Before starting a diagnostic study, first the unit for analysis should be defined in the terms “experimental unit” and “observational unit.”
Discriminant Analysis
Authors: Wernecke Klaus‐D.
Published: October 2006

This article describes discriminant analysis. First, a brief overview is provided followed by discussions of allocation rules and their error rates, Bayes allocation rules, discrimination using normal models, nonparametric discrimination, logistic discriminant analysis, future methods, and judging reliability. Finally, a Section on software packages concludes the article.
Frailty Models
Authors: Wienke Andreas
Published: October 2006

The notion of frailty provides a convenient way to introduce random effects, association, and unobserved heterogeneity into models for survival data. In its simplest form, a frailty is an unobserved random proportionality factor that modifies the hazard function of an individual or related individuals. In essence, the frailty concept goes back to the work of Greenwood and Yule on “accident proneness.” The term frailty itself was introduced by Vaupel et al. in univariate survival models, and the model was substantially promoted by its application to multivariate survival data in a seminal paper by Clayton (without using the notion “frailty”) on chronic disease incidence in families.
Group Sequential Designs
Authors: Wassmer Gernot
Published: October 2006

In clinical research, a great interest in interim analyses exists for ethical, economical, and organizational or administrative reasons. Interim analyses are performed withinsequential designsthat offer the possibility to stop a trial early with a statistically significant test result. This trial will possibly need less patients than the trial with a fixed sample size in which a test decision can be made only at the end of the trial. A therapy that was shown to be superior can be applied earlier and the inferior therapy can be replaced by the better one. Furthermore, in interim analyses, the quality of the performance of the trial can be assessed and possibly be improved when necessary. Interim analyses are also carried out for the assessment of the safety of the treatments under consideration, and the observation of serious adverse events can lead to an early stopping of the trial.
Kaplan–Meier Plot
Authors: Holländer Norbert
Published: October 2006

The Kaplan–Meier plot or Kaplan–Meier curve is the standard method to describe and compare graphically the overall survival of groups of patients. This method is applied to survival time, which is defined as time from treatment start or date of randomization to death or last date of follow up, and, more general, to any type of time‐to‐event data, such as time‐to‐disease progression, time‐to‐detoriation, or time‐to‐first toxicity. Sometimes, the time‐to‐event is also called failure time. In the sequel, the term “survival time” is used as a synonym for any time‐to‐event.
Repeated Measurements
Authors: Verbeke Geert , Lesaffre Emmanuel
Published: October 2006

Repeated measures are obtained whenever an outcome is measured repeatedly within a set of units. The fact that observations from the same unit, in general, will not be independent poses particular challenges to the statistical procedures used for the analysis of such data. The current article is dedicated to an overview of frequently used statistical models for the analysis of repeated measurements, with emphasis on model formulation and parameter interpretation.
Stopping Boundaries
Authors: Leung Denis Heng‐Yan
Published: October 2006

To answer the ethical needs of stopping a clinical trial as soon as it is known that continuing the trial would be inappropriate or unnecessary, trial results are often monitored periodically during the trial. Stopping boundaries are conditions to indicate when results are sufficiently extreme to suggest stopping of the trial.
Linear Model
Authors: Burkholder Iris , Edler Lutz
Published: October 2006

Linear Models for simple and multiple regression, Analysis of Variance (ANOVA), and Analysis of Covariance (ANCOVA) have broad and often direct application in clinical trials. Various extensions and generalizations of the Linear Model have been developed more recently often motivated by medical research problems. Most prominent are the loglinear models for the evaluation of count data; the logistic regression model for the evaluation of the influence of clinical factors on a dichotomous outcome as, for example, cancer incidence; and, last but not least, the Cox regression model for the analysis of survival data.
Hazard Ratio
Authors: Schmoor Claudia , Graf Erika
Published: October 2006

Hazard ratios are useful measures to compare groups of patients with respect to a survival outcome. In the context of clinical trials “survival outcome” or “survival time” are used generically to denote the time “survived” from a specified time origin, like diagnosis of cancer, start of treatment, or first infarction, to a specific event of interest, like death, recurrence of cancer, or reinfarction. Broadly speaking, the hazard rate quantifies the risk of experiencing an event at a given point in time. The hazard ratio at that time is the ratio of this risk in one population divided by the risk in a second population chosen as reference group. The hazard ratio between two populations can vary over time. For a given point in time, hazard ratios below 1.0 indicate that the risk of the event is lower in the first group than the risk in the reference group, whereas a hazard ratio of 1.0 indicates equal risks, and values above 1.0 imply a higher risk in the first group compared with the reference population.
Interim Analyses
Authors: Todd Susan
Published: October 2006

Recruitment of patients to a clinical trial usually occurs over time, resulting in the steady accumulation of data throughout the trial's duration. Yet, if traditional statistical methods are implemented, the sample size of the trial should be determined in advance, and data collected on all subjects should occur before an analysis proceeds. For ethical and economic reasons, techniques of sequential testing incorporating
interim analyses
have been developed to enable the valid examination of accumulating data. The aim is to stop a study as soon as sufficient evidence exists to reach a firm conclusion. Here, the advantages and disadvantages of conducting interim analyses in phase III clinical trials are presented and the development of methodology for interim analyses is chronicled and briefly described. Examples are given of completed trials, which have been carried out incorporating interim analyses, and references to relevant software and literature are provided.
Missing Data
Authors: Molenberghs Geert , Lesaffre Emmanuel
Published: October 2006

Missing data frequently occur in clinical trials. An important source for missing data are patients who leave the study prematurely, so‐called dropouts. We will concentrate here on the impact of dropouts on the clinical trial analysis.

When patients are evaluated under treatment only once, then the presence of dropouts makes it hard to comply with the intention‐to‐treat (ITT) principle. However, when repeated measurements are taken, then one can make use of the observed portion of the data to retrieve information on dropouts. Generally, commonly used methods to analyze incomplete longitudinal clinical trial data include complete case (CC) analysis and a last observation carried forward (LOCF) analysis. However, these methods rest on strong and unverifiable assumptions about the dropout mechanism. Over the last decades, several longitudinal data analysis methods have been suggested, providing a valid estimate for, e.g., the treatment effect under less restrictive assumptions.

The assumptions regarding the dropout mechanism have been classified by Rubin and co‐workers as missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR). We will argue that repeated measures analysis provide valid estimates of the treatment effect under MAR. Finally, as it is impossible to verify that the dropout mechanism is MAR, we argue that, to evaluate the robustness of the conclusion, a sensitivity analysis thereby varying the assumption on the dropout mechanism should become a standard procedure when analyzing the results of a clinical trial.
Ethical Challenges Posed by Cluster Randomization
Authors: Klar Neil , Donner Allan
Published: October 2006

The purpose of this article is to discuss the ethical challenges posed by cluster randomized trials, which is done by revisiting the development of ethical guidelines that have been largely developed in the context of individually randomized clinical trials. A recurring theme underlying the article is that the relative absence of ethical guidelines for cluster randomized trials appears to have created a research environment in which the choice of randomization unit may determine whether informed consent is deemed necessary before random assignment. It seems questionable, on both an ethical level and a methodological level, whether the unit of randomization should play such a critical role in obtaining informed consent. Editors should require all reports of randomized trials to include mention of Institutional Review Board (IRB) approval and to discuss subject consent. For cluster randomized trials, however, additional discussion of procedures used to obtain informed consent is warranted.
Group‐Randomized Trials
Authors: Murray David M.
Published: October 2006

The purpose of this article is to put group‐randomized trials (GRTs) in context in terms of other kinds of designs and in terms of the terminology used in other fields, to summarize their development in public health, to characterize the range of public health research areas that now employ GRTs, to characterize the state of practice with regard to the design and analysis of GRTs, to consider their future in public health research, and to review the steps required to plan a new GRT.
Planning A Group‐Randomized Trial
Authors: Murray David M.
Published: October 2006

Planning a group‐randomized trial (GRT) is a complex process. This article discusses the process behind planning a GRT, including the research question, team, design, potential problems and variables, and intervention.
Methods for Conduct of Rigorous Group‐Randomization
Authors: Peterson Arthur V.
Published: October 2006

A group‐randomized trial (GRT) has two defining characteristics: (
1
) it investigates the effectiveness of a
group
‐delivered intervention, and (
2
) it includes at least one intervention condition and at least one control condition to which
groups
are
randomly
assigned.
1
The groups can be, for example, schools, worksites, clinics, neighborhoods, or even entire towns or cities. Such group‐delivered interventions have advantages of practicality and cost‐efficiency in reaching large numbers of people and, once proven effective, can be important contributions to public health strategy and policy.
Permutation Tests in Clinical Trials
Authors: Zucker David M.
Published: October 2006

This article describes the role of the permutation test as a mechanism for statistically testing treatment effects in a randomized trial without making statistical assumptions beyond those justified by the randomization.
Community‐Based Breast and Cervical Cancer Control Research in Asian Immigrant Populations
Authors: Taylor Victoria M. , Hislop T. Gregory , Yasui Yutaka , Tu Shin‐Ping , Jackson J. Carey
Published: October 2006

Asian‐American women are less likely to receive mammography and Papanicolaou (Pap) testing than women from other racial/ethnic groups. Screening rates are particularly low among Asian women who are not proficient in English. This article focuses on community‐based breast and cervical cancer control research in Asian populations. First, the authors address community participatory research principles and several important program evaluation issues: sampling, survey methods, recruitment and retention, translation, data quality, and control group “contamination.” Second, the authors summarize community‐based studies that aimed to increase mammography or Pap testing levels among women of Asian descent. Overall, 9 relevant studies are identified that targeted Asian communities in Canada, the United States, and England. Overall, three of the studies randomized individual women to intervention or control status, two randomized groups of women, and four used a quasi‐experimental (two‐community) study design. These studies, which reported mixed results, highlight the methodological challenges in conducting evaluative public health research, particularly in racial/ethnic minority communities.
Clinical Trial Misconduct
Authors: Rennie Drummond
Published: October 2006

This article reviews the history and impact of research misconduct. It outlines some of the early cases that prompted standards and legislation. Finally, it discusses recent research abuses within and outside the United States.