A note on fitting one-compartment models: non-linear least squares versus linear least squares using transformed data

Drug concentrations in one-compartment systems are frequently modeled using a single exponential function. Two methods of estimation are commonly used for determining the parameters of such a model. In the first method, non-linear least-squares regression is used to calculate the parameters. In the second method, the data are first transformed by a logarithmic function, and then the log-concentration data are fit using linear least-squares regression. The assumptions for fitting these models are discussed with special emphasis on which data points are most influential in determining parameter values. The similarities between fitting a linear regression model to the log-concentration data and fitting a weighted regression model to the original data are noted. An example is presented that illustrates the differences in fitting a model to the log-transformed data versus fitting unweighted and weighted models to the original-scale data.     

Diversity of trends in occupational injury mortality in the United States, 1980–96

OBJECTIVES: Although the United States has generally enjoyed declining rates of fatal occupational injury, the rate of decline has not been uniform. To examine the heterogeneity of trends, changes in fatal occupational injury rates from 1980 to 1996 were estimated by occupation, industry, geographic region, and demographic group. METHODS: Deaths due to injury at work during 1980-96 were identified from the US National Traumatic Occupational Fatality database and populations at risk were estimated from the census of population. Mortality rates were computed for unintentional injuries, homicides, and all injuries combined. The annual rate of change was estimated using Poisson regression to model the death rate as a function of time. RESULTS: The estimated average rates for all fatal occupational injuries and for unintentional injuries declined by 3% per year, while the estimated rate of homicide declined <1% per year. The improvement was faster for men (3% per year) than for women (<1% per year) and for younger relative to older workers (7% per year v 2%-3% per year). Trends were also geographically heterogeneous, with the most rapid declines (7%-8% per year) in the South and West. Injury rates for most occupations and industries declined at near the average rate, but some experienced no change or an increase. The rate of homicide also increased in a number of occupations and industries. CONCLUSIONS: Broad downward trends in occupational fatality rates may be explained by several factors, including organized safety efforts, product and process changes, and the ongoing shift of employment toward safer sectors. Disparities in fatal injury trends draw attention to potential opportunities to reduce risk: work settings with increasing injury rates are of particular concern.     

Religiosität und Spiritualität im Alter

The present paper presents results regarding religious attitudes and behaviors as well as the perceived social support by religious communities in n = 593 elderly over 60 years (31.2% female, mean age 69.5 years) from the German general population. The results are based on the German 15-item version SBI-15R-D of the "Systems of Belief Inventory" (Holland et al., 1998). Furthermore, religiosity was analyzed as a potential protective factor regarding body complaints in the elderly. Higher scores on religiosity could be found in women compared to men and in elderly from Western Germany compared to those from Eastern Germany. There were no significant correlations between religiosity and body complaints. It is discussed whether the self-ratings of religiosity reflect conventional ideas of a religious orientated person rather than a genuine spiritual attitude.     

Relationship Between Fear of Falling and Outcomes of an Inpatient Geriatric Rehabilitation Population—Fear of the Fear of Falling

OBJECTIVES: To examine the effects of various risk factors on three functional outcomes during rehabilitation. SETTING: Geriatric inpatient rehabilitation unit. DESIGN: Observational longitudinal study. PARTICIPANTS: One hundred sixty‐one geriatric rehabilitation inpatients (men, women), mean age 82, who were capable of walking at baseline. MEASUREMENTS: Functional status was assessed weekly between admission and discharge and at a follow‐up 4 months later at home using the function component of the Short Form—Late Life Function and Disability Instrument, the Barthel Index, and Habitual Gait Speed. Various risk factors, such as falls‐related self‐efficacy (Falls Efficacy Scale–International), were measured. Associations between predictors and functional status at discharge and follow‐up were analyzed using linear regression models and bivariate plots. RESULTS: Fear of falling predicted functioning across all outcomes except for habitual gait speed at discharge and follow‐up. Visual comparison of functional trajectories between subgroups confirmed these findings, with different levels of fear of falling across time in linear plots. Thus, superior ability of this measure to discriminate between functional status at baseline across all outcomes and to discriminate between functional change especially with regard to the performance‐based outcome was demonstrated. CONCLUSION: Falls‐related self‐efficacy is the only parameter that significantly predicts rehabilitation outcome at discharge and follow‐up across all outcomes. Therefore, it should be routinely assessed in future studies in (geriatric) rehabilitation and considered to be an important treatment goal.     

Altered insula response to taste stimuli in individuals recovered from restricting-type anorexia nervosa.

Anorexia nervosa (AN) is an illness characterized by aversion to ingestion of normally palatable foods. We examined whether there is a primary disturbance of taste processing and experience of pleasure using a sucrose/water task in conjunction with functional magnetic resonance imaging (fMRI). To avoid confounding effects of illness, 16 women recovered from restricting-type AN were compared to 16 control women (CW). We used a region of interest-based fMRI approach to test the idea that individuals with AN have differential neural activation in primary and secondary taste cortical regions after sucrose and water administration. Compared to CW, individuals recovered from AN showed a significantly lower neural activation of the insula, including the primary cortical taste region, and ventral and dorsal striatum to both sucrose and water. In addition, insular neural activity correlated with pleasantness ratings for sucrose in CW, but not in AN subjects. Altered taste processing may occur in AN, based on differences in activity in insular-striatal circuits. These data provide the first evidence that individuals with AN process taste stimuli differently than controls, based on differences in neural activation patterns.     

Toxicological safety evaluation of DNA plasmid vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile virus is similar despite differing plasmid backbones or gene-inserts.

The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, and Ebola virus, plus a plasmid cytokine adjuvant-IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, preclinical studies were performed to screen for potential toxicities (intrinsic and immunotoxicities). All treatment-related toxicities identified in these repeated-dose toxicology studies have been confined primarily to the sites of injection and seem to be the result of both the delivery method (as they are seen in both control and treated animals) and the intended immune response to the vaccine (as they occur with greater frequency and severity in treated animals). Reactogenicity at the site of injection is generally seen to be reversible as the frequency and severity diminished between doses and between the immediate and recovery termination time points. This observation also correlated with the biodistribution data reported in the companion article (Sheets et al., 2006), in which DNA plasmid vaccine was shown to remain at the site of injection, rather than biodistributing widely, and to clear over time. The results of these safety studies have been submitted to the Food and Drug Administration to support the safety of initiating clinical studies with these and related DNA plasmid vaccines. Thus far, standard repeated-dose toxicology studies have not identified any target organs for toxicity (other than the injection site) for our DNA plasmid vaccines at doses up to 8 mg per immunization, regardless of disease indication (i.e., expressed gene-insert) and despite differences (strengths) in the promoters used to drive this expression. As clinical data accumulate with these products, it will be possible to retrospectively compare the safety profiles of the products in the clinic to the results of the repeated-dose toxicology studies, in order to determine the utility of such toxicology studies for signaling potential immunotoxicities or intrinsic toxicities from DNA vaccines. These data build on the biodistribution studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications.     

Genome scan for susceptibility loci for schizophrenia

OBJECTIVE: Schizophrenia is a relatively common, often chronic and debilitating mental illness. Evidence from various studies has clearly demonstrated that genetic factors contribute substantially to the etiology. The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes. METHODS: A genome-wide map of 388 microsatellite DNA markers was genotyped in 5 schizophrenia families. Nonparametric linkage analysis (Genehunter) was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease. RESULTS: Nonparametric linkage scores did not reach a genome-wide level of statistical significance (p < 0.00002) or a p value suggestive of linkage (p < 0.007) for any marker; however, one p value suggested replicated linkage (p < 0.01) at chromosome 6p24 in region D6S309 (p = 0.0047). Furthermore, 11 markers resulted in p < 0.05 at chromosomes 6p, 6q, 10q, 12q and 14q. CONCLUSIONS: Despite the differences in diagnostic schemes, in markers used and methods of analyses between studies published so far, we think that our result supports the notion that there is possibly some consistent evidence for replicated linkage of a schizophrenia susceptibility locus around the region of D6S309 at chromosome 6p24.     

123I] beta-CIT and single photon emission computed tomography reveal reduced brain serotonin transporter availability in bulimia nervosa.

BACKGROUND: Impaired serotonin transmission has been implicated in the pathophysiology of eating disorders. We investigated the in vivo availability of brain serotonin transporters and dopamine transporters in bulimia nervosa patients. METHODS: Approximately 24 hours after injection of [123I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I] beta-CIT), single photon emission computed tomography scans were performed in 10 medication-free, female bulimic patients and 10 age-matched, healthy females. For quantification of brain serotonin transporter and dopamine transporter availability, a ratio of specific to nonspecific [123I] beta-CIT brain binding was used (V(3)" = target region - cerebellum/cerebellum). RESULTS: Drug-free bulimia nervosa patients showed a 17% reduced brain serotonin transporter availability in the hypothalamus and thalamus, as compared with healthy control subjects (2.4 +/- 0.4 vs. 2.9 +/- 0.4, p =.026), and a similar reduction in striatal dopamine transporter availability. There was a negative correlation of illness duration and serotonin transporter availability (r = -.65; p =.042) and a strong positive correlation between hypothalamic/thalamic and striatal V(3)" (r =.80, p <.001). CONCLUSIONS: This first report of reduced [123I] beta-CIT binding in a relatively small group of patients with bulimia nervosa suggests a reduced hypothalamic and thalamic serotonin transporter availability in bulimia, which is more pronounced with longer duration of illness.