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PubMed2006

Circulating tumor cells versus imaging--predicting overall survival in metastatic breast cancer.

PURPOSE: The presence of >or=5 circulating tumor cells (CTC) in 7.5 mL blood from patients with measurable metastatic breast cancer before and/or after initiation of therapy is associated with shorter progression-free and overall survival. In this report, we compared the use of CTCs to radiology for prediction of overall survival. EXPERIMENTAL DESIGN: One hundred thirty-eight metastatic breast cancer patients had imaging studies done before and a median of 10 weeks after the initiation of therapy. All scans were centrally reviewed by two independent radiologists using WHO criteria to determine radiologic response. CTC counts were determined approximately 4 weeks after initiation of therapy. Specimens were analyzed at one of seven laboratories and reviewed by a central laboratory. RESULTS: Interreader variability for radiologic responses and CTC counts were 15.2% and 0.7%, respectively. The median overall survival of 13 (9%) patients with radiologic nonprogression and >or=5 CTCs was significantly shorter than that of the 83 (60%) patients with radiologic nonprogression and <5 CTCs (15.3 versus 26.9 months; P=0.0389). The median overall survival of the 20 (14%) patients with radiologic progression and <5 CTCs was significantly longer than the 22 (16%) patients with >or=5 CTCs that showed progression by radiology (19.9 versus 6.4 months; P=0.0039). CONCLUSIONS: Assessment of CTCs is an earlier, more reproducible indication of disease status than current imaging methods. CTCs may be a superior surrogate end point, as they are highly reproducible and correlate better with overall survival than do changes determined by traditional radiology.

Breast Neoplasms↗

PubMed1996

Male sexual behavior and human papillomavirus DNA: key risk factors for cervical cancer in Spain.

BACKGROUND: It is now established that certain types of human papillomaviruses (HPVs) are the sexually transmitted agents etiologically linked to cervical cancer. Studies assessing the contribution of the male's sexual behavior and genital HPV DNA status to the risk of development of cervical neoplasia in sexual partners have yielded inconsistent results. PURPOSE: This study evaluates the role of men's sexual behavior and the presence of HPV DNA in the penis on the development of cervical cancer in their sexual partners in Spain, a low-risk area for cervical neoplasia. METHODS: Husbands (n = 633) of women participating in two case-control studies of cervical neoplasia were interviewed to obtain information on lifestyle habits, including sexual practices. Cytologic samples were taken from the distal urethra and the surface of the glans penis of 183 husbands of case women and of 171 husbands of control women. These samples were analyzed by a polymerase chain reaction-based system using a generic probe and 25 type-specific probes for the detection and typing of HPV DNA. Serologic specimens were also obtained and analyzed for antibodies to Chlamydia trachomatis, Treponema pallidum, herpes simplex virus type II, and Neisseria gonorrhoeae. RESULTS: The presence of HPV DNA in the husbands' penis conveyed a fivefold risk of cervical cancer to their wives (adjusted odds ratio [OR] for HPV DNA positivity = 4.9; 95% confidence interval [CI] = 1.9-12.6). The risk of cervical cancer was strongly related to HPV type (adjusted OR for HPV type 16 = 9.0; 95% CI = 1.1-77.5), to the husbands' number of extramarital partners (adjusted OR = 11.0; 95% CI = 3.0-40.0; for > or = 21 women versus one), and to the number of prostitutes as extramarital sexual partners (adjusted OR = 8.0; 95% CI = 2.9-22.2; for > or = 10 women versus none). Presence of antibodies to C. trachomatis (adjusted OR = 2.6; 95% CI = 1.4-4.6) and an early age at first sexual intercourse of the husband (adjusted OR = 3.2; 95% CI = 1.7-5.9; for < or = 15 years versus > or = 21 years) were also associated with cervical neoplasia in the wife. After adjustment for these variables and for the wife's pack-years of smoking, the husband's smoking was moderately associated with cervical cancer in his wife (adjusted OR = 2.5; 95% CI = 1.4-4.4; for > or = 26.2 pack-years versus none). CONCLUSIONS: The study supports the role of men as vectors of the HPV types that are related to cervical cancer. Life-time number of female sexual partners, number of female prostitutes as sexual partners, and detection of HPV DNA in the penis of husbands are all surrogate markers of exposure to HPV during marriage. IMPLICATIONS: Men who report multiple sexual partners or who are carriers of HPV DNA may be vectors of high-risk HPV types and may place their wives at high risk of developing cervical cancer. Prostitutes are an important reservoir of high-risk HPVs.

Carcinoma, Squamous Cell↗

PubMed1990

Correction of logistic regression relative risk estimates and confidence intervals for measurement error: the case of multiple covariates measured with error.

If several risk factors for disease are considered in the same multiple logistic regression model, and some of these risk factors are measured with error, the point and interval estimates of relative risk corresponding to any of these factors may be biased either toward or away from the null value. A method is provided for correcting point and interval estimates of relative risk obtained from logistic regression for measurement error in one or more continuous variables. The method requires a separate validation study to estimate the coefficients from the multivariate linear regression model relating the surrogate variables to the vector of true risk factors. Similar methods have been suggested by other authors, but none provides a means of correcting the confidence intervals which include a component of variability due to estimation of the measurement error parameters from a validation study. An example is provided from a prospective study of dietary fat, calories, and alcohol in relation to breast cancer, and from a validation study of the questionnaire used to assess these nutrients. Before correcting for measurement error, the age-adjusted relative risk for a 25 g increment in alcohol intake was 1.33 (95% confidence interval (CI) 1.14-1.55); after correcting for measurement error, the relative risk increased to 1.62 (95% CI 1.23-2.12). Similarly, for a 10 g increment in saturated fat intake, the age-adjusted relative risk was 0.94 (95% CI 0.83-1.06); after correcting for measurement error, the relative risk was 0.84 (95% CI 0.59-1.20). These results indicate that the failure to find a substantial positive association between breast cancer risk and saturated fat intake cannot be explained by measurement error in fat, calories, or alcohol.

Bias↗

PubMed1997

Gastric intramucosal pH changes after volume replacement with hydroxyethyl starch or crystalloid in patients undergoing elective abdominal aortic aneurysm repair.

PURPOSE: Gastric intramucosal pH (pHi), a surrogate marker of tissue oxygenation, falls following abdominal aorta aneurysm (AAA) repair. We tested the hypothesis that volume replacement with a hydroxyethyl starch solution would result in better preserved splanchnic oxygenation than would volume replacement with crystalloid solutions. MATERIALS AND METHODS: This was a prospective, randomized, nonblinded study set in a university-affiliated community hospital. Thirty patients undergoing elective AAA repair were studied. Patients were randomly selected to receive intraoperative and postoperative fluid replacement with either hetastarch or crystalloid. According to the study protocol, patients could not receive in excess of 3,000 mL of hetastarch. Tissue oxygenation was assessed indirectly by measuring pHi using a nasogastric tonometer. Hemodynamic, oxygenation, and pHi data were collected preoperatively, preclamp, before unclamping, at the end of the procedure and postoperatively for 24 hours. Coagulation parameters were determined preoperatively and postoperatively for 24 hours. RESULTS: Fifteen patients were randomized to each group. There were 18 male and 12 female patients, whose mean age was 66 +/- 9 years. The intraoperative fluid balance was significantly greater in the crystalloid compared with the hetastarch group (4,194 +/- 1,500 mL v 2,949 +/- 1,123 mL; P = .05, 95% confidence interval [C] 23 to 2,519 mL). There were no significant differences in the amount of intraoperative blood loss or postoperative transfusion requirements between the two groups. The difference between the preoperative pHi and nadir was 0.07 +/- 0.03 in the hetastarch group compared with 0.13 +/- 0.04 in the crystalloid group (P = .001, Cl 0.03 to 0.09). By multivariate analysis the only variable that influenced the fall in pHi was the type of resuscitation fluid (F ratio of 7.63; P = .01). There were no significant differences in hemodynamic- and oxygenation-derived variables or coagulation parameters between the two groups of patients. The length of mechanical ventilation, intensive care unit, and hospital stay was comparable between the two groups of patients. CONCLUSION: In patients undergoing major surgery, volume resuscitation with hydroxyethyl starch solutions may improve microvascular blood flow and tissue oxygenation.

Aged↗

PubMed2006

An administrative claims model suitable for profiling hospital performance based on 30-day mortality rates among patients with an acute myocardial infarction.

BACKGROUND: A model using administrative claims data that is suitable for profiling hospital performance for acute myocardial infarction would be useful in quality assessment and improvement efforts. We sought to develop a hierarchical regression model using Medicare claims data that produces hospital risk-standardized 30-day mortality rates and to validate the hospital estimates against those derived from a medical record model. METHODS AND RESULTS: For hospital estimates derived from claims data, we developed a derivation model using 140,120 cases discharged from 4664 hospitals in 1998. For the comparison of models from claims data and medical record data, we used the Cooperative Cardiovascular Project database. To determine the stability of the model over time, we used annual Medicare cohorts discharged in 1995, 1997, and 1999-2001. The final model included 27 variables and had an area under the receiver operating characteristic curve of 0.71. In a comparison of the risk-standardized hospital mortality rates from the claims model with those of the medical record model, the correlation coefficient was 0.90 (SE=0.003). The slope of the weighted regression line was 0.95 (SE=0.007), and the intercept was 0.008 (SE=0.001), both indicating strong agreement of the hospital estimates between the 2 data sources. The median difference between the claims-based hospital risk-standardized mortality rates and the chart-based rates was <0.001 (25th and 75th percentiles, -0.003 and 0.003). The performance of the model was stable over time. CONCLUSIONS: This administrative claims-based model for profiling hospitals performs consistently over several years and produces estimates of risk-standardized mortality that are good surrogates for estimates from a medical record model.

Aged↗

PubMed2001

Body mass index and mortality in an insured population.

OBJECTIVE: This study was conducted to explore the relationship between body mass index (BMI) and mortality in an insured population issued policies at standard rates or rated only for build using contemporary analytic techniques. BACKGROUND: Many factors influence the relationship between build and mortality. Recent clinical literature on this subject often employs multivariate statistical techniques to better define this relationship and reduce the influence of confounders. BMI, a common surrogate variable for build in clinical literature, is our variable of choice in studying the relationship between build and mortality. METHODS: We studied internal data on direct and reinsurance business issued between 1975 and 1998 at standard rates or rated only for build. The policies were followed till termination (death or lapse) or to the end of 1999. The average policy duration was 4.7 years. Cox proportional hazards model runs were used to study the multivariate relationship between mortality and BMI in moderately over- and underweight insured individuals. RESULTS: During follow-up, 4105 deaths were observed. Mortality was noted to very with BMI, most significantly in middle-aged male nonsmokers. Consistent with reports from the clinical literature, significant factors influencing the BMI-mortality relationship in this insured population included issue age and smoking status. CONCLUSIONS: BMI is a predictor of statistically significant mortality differentials in insured populations. The strength of the BMI-mortality relationship was found to vary by age, gender, and smoking status. In our study population, the male nonsmoker subgroups tended to exhibit the strongest graded relationship between hazard of death and increasing or decreasing BMI.

Adolescent↗

PubMed2003

Outcome prediction in a surgical ICU using automatically calculated SAPS II scores.

The objective of this study was to establish a complete computerized calculation of the Simplified Acute Physiology Score (SAPS) II within 24 hours after admission to a surgical intensive care unit (ICU) based only on routine data recorded with a patient data management system (PDMS) without any additional manual data entry. Score calculation programs were developed using SQL scripts (Structured Query Language) to retrospectively compute the SAPS II scores of 524 patients who stayed in ICU for at least 24 hours between April 1, 1999 and March 31, 2000 out of the PDMS database. The main outcome measure was survival status at ICU discharge. Score evaluation was modified in registering missing data as being not pathological and using surrogates of the Glasgow Coma Scale (GCS). Computerized score calculation was possible for all investigated patients. The 459 (87.6%) survivors had a median SAPS II of 28 (interquartile range (IQR) 13) whereas the 65 (12.4%) decreased patients had a median score of 43 (IQR 16; P < 0.001). Of the physiological variables for SAPS II score calculation, bilirubin was missing in 84%, followed by PaO2/FiO2 ratio (34%), and neurological status (34%). Using neurological diagnoses and examinations as surrogates for the GCS, a pathological finding was seen in only 8.8% of all results. The discriminative power of the computerized SAPS II checked with a receiver operating characteristic (ROC) curve was 0.81 (95% confidence interval (CI): 0.74-0.87). The Hosmer-Lemeshow goodness-of-fit statistics showed good calibration (H = 5.55, P = 0.59, 7 degrees of freedom; C = 5.55, P = 0.68, 8 degrees of freedom). The technique used in this study for complete automatic data sampling of the SAPS II score seems to be suitable for predicting mortality rate during stay in a surgical ICU. The advantage of the described method is that no additional manual data recording is required for score calculation.

Adult↗

PubMed2005

Relationship between plasma lipids and all-cause mortality in nondemented elderly.

OBJECTIVES: To investigate the relationship between plasma lipids and risk of death from all causes in nondemented elderly. DESIGN: Prospective cohort study. SETTING: Community-based sample of Medicare recipients, aged 65 years and older, residing in northern Manhattan. PARTICIPANTS: Two thousand two hundred seventy-seven nondemented elderly, aged 65 to 98; 672 (29.5%) white/non-Hispanic, 699 (30.7%) black/non-Hispanic, 876 (38.5%) Hispanic, and 30 (1.3%) other. MEASUREMENTS: Anthropometric measures: fasting plasma total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-HDL-C, body mass index, and apolipoprotein E (APOE) genotype. clinical measures: neuropsychological, neurological, medical, and functional assessments; medical history of diabetes mellitus, heart disease, hypertension, stroke, and treatment with lipid-lowering drugs. Vital status measure: National Death Index date of death. Survival methods were used to examine the relationship between plasma lipids and subsequent mortality in younger and older nondemented elderly, adjusting for potential confounders. RESULTS: Nondemented elderly with levels of total cholesterol, non-HDL-C, and LDL-C in the lowest quartile were approximately twice as likely to die as those in the highest quartile (rate ratio (RR)=1.8, 95% confidence interval (CI)=1.3-2.4). These results did not vary when analyses were adjusted for body mass index, APOE genotype, diabetes mellitus, heart disease, hypertension, stroke, diagnosis of cancer, current smoking status, or demographic variables. The association between lipid levels and risk of death was attenuated when subjects with less than 1 year of follow-up were excluded (RR=1.4, 95% CI=1.0-2.1). The relationship between total cholesterol, non-HDL-C, HDL-C, and triglycerides and risk of death did not differ for older (>or=75) and younger participants (>75), whereas the relationship between LDL-C and risk of death was stronger in younger than older participants (RR=2.4, 95% CI=1.2-4.9 vs RR=1.6, 95% CI=1.02-2.6, respectively). Overall, women had higher mean lipid levels than men and lower mortality risk, but the risk of death was comparable for men and women with comparable low lipid levels. CONCLUSION: Low cholesterol level is a robust predictor of mortality in the nondemented elderly and may be a surrogate of frailty or subclinical disease. More research is needed to understand these associations.

Aged↗

PubMed2004

Susceptibility of residential wells to VOC and nitrate contamination.

Water quality of residential wells is vital to public health and a complex issue for regulatory agencies. South Carolina, a typical southeastern rural state, has no required testing of residential well water quality after initial well construction. This study used site-selection criteria to identify susceptible residential wells based on a combination of geologic vulnerability and potential contaminant loading. Geologic vulnerability was defined as increased probability of contaminants being transported from the land surface into the groundwater based on geological properties. As a surrogate for potential general contaminant loading, wells were located within 800 m of an EPA Toxics Release Inventory facility reporting VOC emissions, thus sampling was nonrandom. Seventy private residential wells were sampled for volatile organic compounds (VOCs) and nitrate-nitrogen (NO3-N) and analyzed using gas chromatography/mass spectrometry and the cadmium reduction method, respectively. Geographic Information Systems (GIS) was used to quantify four explanatory variables that affect well susceptibility to nitrate: population density, land cover, local relief (percent slope), and soil texture. VOCs were detected in 11 wells, and two sites exceeded the MCL for 1,1-dichloroethylene (36.1 microg/L) and trichloroethylene (9.0 microg/L). Elevated NO3-N (defined as > or = 1.0 mg/L) was measured in 20 wells. Logistic regression identified grassland/cultivated land cover as a variable that significantly increased the probability of NO3-N contamination (p = 0.003). Using easily accessible databases to identify factors that increase the probability of groundwater pollution could lead to more effective programs for locating residential wells that are susceptible to contamination. Increased monitoring of well water quality, as is being considered in some states, is warranted to reduce potential human exposure to contaminated drinking water.

Agriculture↗

PubMed2003

A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers.

BACKGROUND: Tamoxifen reduces the risk of breast cancer in women at high risk for the disease but increases the risk for endometrial tumors and venous thromboembolisms, possibly in a dose-dependent fashion. We compared the effects of tamoxifen at 1 mg/day and 5 mg/day with those of the standard dose of 20 mg/day on breast cancer proliferation using a surrogate endpoint marker (Ki-67 expression) and blood biomarkers associated with breast cancer, cardiovascular disease, and bone fracture risk. METHODS: We randomly assigned 120 women with estrogen receptor (ER)-positive breast cancer to tamoxifen at 1, 5, or 20 mg/day for 4 weeks. Expression of the tumor proliferation marker Ki-67 and of biomarkers of breast cancer (insulin-like growth factor-I, sex hormone-binding globulin), cardiovascular disease (cholesterol, triglycerides, ultrasensitive C-reactive protein, fibrinogen, antithrombin-III), and bone fracture (type I collagen C-telopeptide) risk were determined before (baseline) and after treatment. All levels were compared with those in two nonrandomized control groups (34 women with ER-negative breast cancer and 29 additional women with ER-positive breast cancer). Data were analyzed by analysis of covariance. All statistical tests were two-sided. RESULTS: Expression of Ki-67 decreased in all three tamoxifen groups, with no difference in the magnitude of reduction among groups (P =.81). Relative to baseline, Ki-67 expression decreased by a median of 15.0% (95% confidence interval = 0.0% to 24.1%) among the tamoxifen groups but increased by 12.8% (95% confidence interval = 0.0% to 19.6%) among the nonrandomized control groups. Several blood biomarkers showed dose-response relationships with tamoxifen, including decreased insulin-like growth factor-I, increased sex hormone-binding globulin, and decreased low-density lipoprotein-cholesterol, ultrasensitive C-reactive protein, fibrinogen, and antithrombin-III levels. CONCLUSIONS: The effects on Ki-67 expression of lower doses of tamoxifen were comparable to those achieved with the standard dose, although the effects on blood biomarkers were variable. The effects of lower doses of tamoxifen should be assessed further in randomized trials.

Adult↗

PubMed1996

The VDJ repertoire expressed in human preB cells reflects the selection of bona fide heavy chains.

In early steps of B cell differentiation, mu chains are transiently expressed in association with a surrogate light chain (psi L) composed of the lambda-like and VpreB monomorphic polypeptides, thus forming a putative preB receptor. Using a monoclonal anti-VpreB antibody, preB cells were isolated from two adult human bone marrow samples and their VDJ repertoire analyzed at the transcription level. All VH families were identified and further analysis focused on VH3 sequence analysis of 37 distinct VDJ cDNA clones. The VH3 genes expressed in the two bone marrow samples were also encountered in fetal liver and adult peripheral blood lymphocytes with a roughly similar contribution of 3.30, 3.23, 3.9 and 3.53. The characteristic features of the preB repertoire as compared to the activation B repertoire include the quasi absence of somatic mutations, limited N diversity and a shorter third complementarity-determining region (CDR3). It also significantly differs from the fetal repertoire, which makes higher usage of DQ52 and has CDR3 of even shorter lengths. The almost constant presence of glycine residues in the CDR3 and predominance of JH4 with a low level of DQ52 DH usage, suggest that preB cell clones are submitted to an initial selective pressure which should be antigen independent. The bona fide heavy chains would be merely selected for their ability to interact with the surrogate light chains, thus shaping the repertoire that will be co-expressed with immunoglobulin light chains in IgM molecules.

Adult↗

PubMed2006

Persisting effects on fasting glucose levels and insulin sensitivity after 6 months of discontinuation of a very low-dose GH therapy in adults with severe GH deficiency.

OBJECTIVE: We recently reported that, in contrast to the standard GH (SGH) replacement dose titrated to normalize serum IGF-I levels, 12-month treatment with a fixed low GH dose (LGH) (0.1 mg/day) decreased fasting glucose levels and improved insulin sensitivity with little effect on body composition in severely GH-deficient adults. In this study, we have subsequently examined the effects after 6 months of discontinuation of these variable GH doses (LGH: n = 8; fixed dose 0.10 mg/day and SGH: n = 8; mean dose 0.50 mg/day) on glucose metabolism, body composition and other surrogate cardiovascular risk markers. METHODS: Fasting insulin sensitivity using the homeostasis model assessment, and body composition using dual-energy X-ray absorptiometry scans were assessed at baseline, after 12 months of therapy (month 12) and after 6 months following discontinuation of therapy (month 18). RESULTS: At month 12, the LGH decreased fasting glucose levels and improved insulin sensitivity without altering body composition, whereas the SGH improved body composition without modifying insulin sensitivity. Six months after discontinuation of the LGH treatment (month 18), fasting glucose levels remained decreased and the enhanced insulin sensitivity persisted. In contrast, after discontinuation of SGH treatment (month 18), body composition reverted to baseline without changes in either fasting glucose levels or insulin sensitivity. CONCLUSION In contrast to the SGH, the LGH induces effects on fasting glucose levels and insulin sensitivity, which persist after 6 months of discontinuation of therapy. The exact molecular mechanisms are unclear but may involve the modulation of hepatic and muscle insulin sensitivity, possibly by altering insulin and IGF-I receptor responsiveness and/or density.

Adult↗

PubMed1995

Development and evaluation of the specificity of a rat monoclonal anti-idiotype antibody, WN, to an anti-B-cell lymphoma monoclonal antibody, LL2.

Anti-idiotype monoclonal antibodies (Mabs) to mLL2, an anti-B-cell lymphoma and CD22-specific murine IgG2a-kappa Mab, were generated by hybridoma technology from splenocytes of Copenhagen rats immunized with mLL2 F(ab')2. Mab WN, an IgG2a-kappa, was selected based on its specific binding to mLL2 and not other IgG isotypes or anti-B-cell Mabs. In a radioimmunoassay, WN was found to inhibit the binding of 125I-labeled mLL2 to Raji cells and to have no effect on the binding of other B-cell-reactive antibodies. Using high performance liquid chromatography analysis, WN was shown to complex specifically with both mLL2 and mLL2 Fab'. Meanwhile, we have constructed chimeric (cLL2) and humanized (hLL2) versions of LL2. Both cLL2 and hLL2 were demonstrated to retain the original antigen specificity and affinity of mLL2 [S.O. Leung et al., Proc. Am. Assoc. Cancer Res., 2872 (abstract), 34: 481, 1993]. The specific binding of WN to either radioiodinated or peroxidase-conjugated mLL2 was inhibited in a dose-response manner, and to a similar extent by mLL2, cLL2, and hLL2. Since the mLL2 complementarity-determining regions are the only sequences common to mLL2, cLL2, and hLL2, the result confirms that WN is specific to the antigen-binding complementarity-determining regions. A WN binding assay is currently being evaluated as a substitute for the tedious, and sometimes inconsistent, Raji cell-binding assay for the determination of LL2 immunoreactivity. In conclusion, we have developed an anti-idiotype Mab, WN, to mLL2. Its potential use as a surrogate antigen for B-cell lymphoma is under investigation.

Animals↗

PubMed2001

Biochemical (and functional) imaging of articular cartilage.

Over the coming decades nondestructive biochemical imaging by magnetic resonance imaging (MRI) will provide an adjunct or surrogate for the destructive histologic and biochemical assays used today. A number of MRI methods demonstrate image contrast that, although influenced by the biochemical composition, is not normally specific to a particular measure of the biochemical state. The most widely used of these is T2-weighted imaging, which variably reveals collagen ultrastructure, hydration (or collagen content), and, to a lesser extent, glycosaminoglycan (GAG) concentration (each of these biochemical metrics is an important determinant of the functional integrity of cartilage). The lack of specificity of this technique (and others discussed herein) confounds efforts to improve strategies for evaluating cartilage. However, three methods permit a very specific measure of the cartilage biochemical state. Each of these three methods, explored in detail in this article, is rooted in a biophysical theory that relates the image signal intensity to a specific biochemical feature. Proton-density imaging directly measures water content (hydration), a parameter that might increase approximately 5% with significant degeneration. Magic-angle imaging, in which the angle dependence of T2 is measured, can provide a specific measure of collagen (or macromolecular) ultrastructure. The difficulty in getting the angle dependence presently precludes its use clinically. Delayed gadolinium-enhanced MRI of cartilage provides a specific measure of the distribution of GAGs. This method measures the distribution of a charged contrast agent, which in turn reflects the distribution of charge associated with GAG. This technique can be used in a clinical setting, and ongoing studies will explore its utility in monitoring therapeutic efficacy and disease progression. Although none of these techniques are presently in routine clinical use, emerging data provide promise that the future will see patient-specific biochemical analysis of cartilage, an outcome almost unimaginable 20 years ago.

Biomechanical Phenomena↗

PubMed2006

Identifying perinatal risk factors for infant maltreatment: an ecological approach.

BACKGROUND: Child maltreatment and its consequences are a persistent problem throughout the world. Public health workers, human services officials, and others are interested in new and efficient ways to determine which geographic areas to target for intervention programs and resources. To improve assessment efforts, selected perinatal factors were examined, both individually and in various combinations, to determine if they are associated with increased risk of infant maltreatment. State of Georgia birth records and abuse and neglect data were analyzed using an area-based, ecological approach with the census tract as a surrogate for the community. Cartographic visualization suggested some correlation exists between risk factors and child maltreatment, so bivariate and multivariate regression were performed. The presence of spatial autocorrelation precluded the use of traditional ordinary least squares regression, therefore a spatial regression model coupled with maximum likelihood estimation was employed. RESULTS: Results indicate that all individual factors or their combinations are significantly associated with increased risk of infant maltreatment. The set of perinatal risk factors that best predicts infant maltreatment rates are: mother smoked during pregnancy, families with three or more siblings, maternal age less than 20 years, births to unmarried mothers, Medicaid beneficiaries, and inadequate prenatal care. CONCLUSION: This model enables public health to take a proactive stance, to reasonably predict areas where poor outcomes are likely to occur, and to therefore more efficiently allocate resources. U.S. states that routinely collect the variables the National Center for Health Statistics (NCHS) defines for birth certificates can easily identify areas that are at high risk for infant maltreatment. The authors recommend that agencies charged with reducing child maltreatment target communities that demonstrate the perinatal risks identified in this study.

Child Abuse↗

PubMed2003

Predicting major neurological improvement with intravenous recombinant tissue plasminogen activator treatment of stroke.

BACKGROUND AND PURPOSE: In the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study, major neurological improvement within 24 hours (MNI) occurred significantly more frequently with recombinant tissue plasminogen activator (rtPA) treatment than with placebo. We explored the relationship between MNI and 3-month favorable outcome and sought clinical predictors of MNI. METHODS: Data from 312 rtPA-treated patients from the NINDS trial were used to assess the ability of MNI to predict favorable outcome at 3 months as defined by a modified Rankin Scale score of 0 to 1. Next, a multivariable predictive model was developed for MNI within the same data set. Clinical variables examined included age, time to treatment (TTT), diabetes, pretreatment glucose, baseline National Institutes of Health Stroke Scale score, pretreatment blood pressure, history of atrial fibrillation, weight >100 kg, and a dense artery sign. Finally, this model was used to forecast into the placebo group of the NINDS trial to assess the uniqueness of the predictors in the rtPA-treated group. RESULTS: MNI had a positive predictive value and negative predictive value of 0.70 for predicting favorable 3-month outcome. Only age [odds ratio (OR), 0.68; 95% confidence interval (CI), 0.47 to 0.99] and TTT (OR, 0.56; 95% CI, 0.34 to 0.91) appear to be independently associated with MNI. The model performed only moderately well (area under the receiver-operating characteristic curve, 0.66). Age (OR, 0.67; 95% CI, 0.45 to 0.99) but not TTT was associated with MNI in the placebo group. CONCLUSIONS: MNI may be a useful surrogate for thrombolytic activity and is predictive of favorable 3-month outcome. When rates of MNI in different populations of stroke patients treated with thrombolysis are compared, adjustments for age and TTT may be necessary.

Age Factors↗

PubMed2006

Functional outcome and prognostic factors in 304 eyes managed by retinectomy.

BACKGROUND: This study was undertaken to relate the anatomic and functional results of patients who underwent retinectomy for complex retinal detachment (RD) to preoperative prognostic variables. METHODS: Three hundred and four eyes of 302 patients whose surgery involved retinectomy were included in the analysis. All eyes had established proliferative vitreoretinopathy (PVR grade C). The main outcome measures were (1) postoperative visual acuity of 6/24 or better, (2) status of the retina at the end of follow-up, and (3) incidence of hypotony whilst under review. RESULTS: PVR was secondary to rhegmatogenous RD in 237 eyes (78%), posterior trauma in 51 eyes (16.8%), tractional RD in vasoproliferative vasculitides in 12 eyes (4%), acute retinal necrosis in 2 eyes and endophthalmitis in 2 eyes. Complete reattachment rate after one operation was 51%, with final complete reattachment success rate of 72%. The visual acuity improved in 138 eyes (45%), remained the same in 73 eyes (24%) and became worse in 89 cases (29%). Postoperative visual acuity of 6/24 or better was significantly associated with preoperative vision, the duration of silicone oil tamponade, silicone oil removal and retinectomy size. There was also some evidence of association between visual outcome and the number of clock hours of retinal detachment. Final retinal attachment was significantly associated with silicone oil removal and preoperative vision, and final hypotony was significantly associated with silicone oil removal. The incidence of sympathetic ophthalmia in our study was 0.09% (one case). CONCLUSIONS: Good functional outcome is possible following retinectomy surgery despite advanced pathology and often multiple surgical procedures. Retinal redetachment as a result of reproliferation and hypotony appear to be the main reasons for anatomical and functional failure. The clinical features we have identified as good indicators for improved final visual acuity such as shorter tamponade duration, removal of silicone oil, smaller retinectomy size, fewer previous operations and better preoperative vision are surrogate markers of less advanced PVR and should prompt retinal surgeons to consider retinectomy at an earlier stage in the process of PVR development. Clinicians should be aware of the small risk of sympathetic ophthalmia from complex retinal surgery.

Adolescent↗

PubMedDate not supplied

Pharmacometrics: modelling and simulation tools to improve decision making in clinical drug development.

There is broad recognition within the pharmaceutical industry that the drug development process, especially the clinical part of it, needs considerable improvement to cope with rapid changes in research and health care environments. Modelling and simulation are mathematically founded techniques that have been used extensively and for a long time in other areas than the pharmaceutical industry (e.g. automobile, aerospace) to design and develop products more efficiently. Both modelling and simulation rely on the use of (mathematical and statistical) models which are essentially simplified descriptions of complex systems under investigation. It has been proposed to integrate pharmacokinetic (PK) and pharmacodynamic (PD) principles into drug development to make it more rational and efficient. There is evidence from a survey on 18 development projects that a PK/PD guided approach can contribute to streamline the drug development process. This approach extensively relies on PK/PD models describing the relationships among dose, concentration (and more generally exposure), and responses such as surrogate markers, efficacy measures, adverse events. Well documented empirical and physiologically based PK/PD models are becoming available more and more, and there are ongoing efforts to integrate models for disease progression and patient behavior (e.g. compliance) as well. Other types of models which are becoming increasingly important are population PK/PD models which, in addition to the characterization of PK and PD, involve relationships between covariates (i.e. patient characteristics such as age, body weight) and PK/PD parameters. Population models allow to assess and to quantify potential sources of variability in exposure and response in the target population, even under sparse sampling conditions. As will be shown for an anticancer agent, implications of significant covariate effects can be evaluated by computer simulations using the population PK/PD model. Stochastic simulation is widely used as a tool for evaluation of statistical methodology including for example the evaluation of performance of measures for bioequivalence assessment. Recently, it was suggested to expand the use of simulations in support of clinical drug development for predicting outcomes of planned trials. The methodological basis for this approach is provided by (population) PK/PD models together with random sampling techniques. Models for disease progression and behavioral features like compliance, drop-out rates, adverse event dependent dose reductions, etc. have to be added to population PK/PD models in order to mimic the real situation. It will be shown that computer simulation helps to evaluate consequences of design features on safety and efficacy assessment of the drug, enabling identification of statistically valid and practically realisable study designs. For both modelling and simulation a guidance on 'best practices' is currently worked out by a panel of experts comprising representatives from academia, regulatory bodies and industry, thereby providing a necessary condition that model-based analysis and simulation will further contribute to streamlining pharmaceutical drug development processes.

Clinical Trials as Topic↗