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PubMed1997

Conceptualizing services research on outpatient commitment.

Issues affecting the research of outcomes of involuntary outpatient commitment (OC) of persons with serious mental illness are explored. These issues include the reliance on hospital recidivism as a primary measure of outcome, the role of family members and coercion in the process of outpatient commitment, and the conceptualization and design of studies. A conceptual framework that attempts to incorporate responses to these issues is proposed. Continued research on OC should build on conceptual models that include family role and burden, services delivered, an accounting for varied coercive mechanisms, and client-level outcomes. Rehospitalization should be conceptualized as an intermediate variable between OC and client-level outcomes rather than as an ultimate outcome.

Ambulatory Care↗
PubMed1997

Identification, cloning and sequence analysis of the equine adenovirus 1 hexon gene.

Based on sequence homology with human adenovirus 2 (HAdV2), the hexon gene of equine adenovirus 1 (EAdV1) was identified. HindIII restriction fragments containing the hexon and other viral genes were cloned into the plasmids pUC19 and pBlueScript SK(-) and sequenced. The nucleotide sequence of the hexon gene was completely determined and partial sequence data were obtained for seven other EAdV1 genes. Amino acid (aa) sequence comparison with published adenovirus (AdV) proteins identified the genes for the IIIa, penton, pVII, PVI, 23K proteinase, DNA binding and 100K proteins. The eight EAdV1 genes appeared to be in the same relative order as homologous genes of other AdV. The EAdV1 hexon protein was encoded between the hexon-associated pVI upstream and the 23K proteinase gene downstream and comprised 2742 nucleotides which translated into 913 aa. Similar to other members of the genus Mastadenovirus the EAdV1 hexon yielded two highly conserved genome segments at the N- and C-termini which flanked intermediate variable and hypervariable regions. The majority of the residue differences between EAdV1 and other AdV hexons occurred in two loops that are known for other AdV to protrude from the surface of the nucleocapsid. Amino acid comparisons with other AdV hexons revealed highest homology with HAdV12 hexon with 72% identical and 83% functionally similar residues, followed by bovine AdV3 hexon with 71% identities and 82% functional residue conservation. Phylogenetic analysis suggested that EAdV1 and other AdV do not have an immediate common ancestor.

Amino Acid Sequence↗
PubMed1986

Encouraging the development of integrated health centres: a critical analysis of lower referral rates.

Dutch government policy places considerable emphasis on the strengthening of the primary health care sector. In this connection, it has been shown that health centres tend to reduce costs. The referral rate for GPs in health centres is considerably lower than for GPs practising alone. The question this raises is whether the lower rates are due to the performance of the GPs or to intermediate variables. Three research projects which cast some light on this issue are examined. The first dealt with a possible explanation by means of structural variables, such as differences in the level of urbanization and the availability of hospital services. The second addressed itself to the question of 'patient mix' and asked whether this is responsible for differences in referral rates, which the third project put the same question in respect to the selection of physicians. All results supported rejection of the hypothesis that the statistical relation between the practice-setting and the referral rate was spurious. A clear result concerning the causality of the relation is not yet available.

Adolescent↗
PubMed1985

Sequence of the viral replicase gene from foot-and-mouth disease virus C1-Santa Pau (C-S8).

The nucleotide sequence of the region including the viral replicase gene, the carboxy terminus of protein P18, and the 3'-extracistronic region of foot-and-mouth disease virus (FMDV) type C1-Santa Pau (C-S8) has been determined from previously cloned cDNA fragments [Villanueva et al., Gene 23 (1983) 185-194]. The comparison with the corresponding gene segments of FMDV of serotypes A or O shows base substitutions in 7.2-8.6% of residues in the replicase gene with no insertions or deletions. This is about fourfold lower variation than found for the region encoding capsid protein VP1 of the corresponding viruses. Intermediate variability (substitution at 16.1-23.6% positions) exists in the 3'-extracistronic region, including point mutations, insertions and deletions. The predicted amino acid sequence of the replicase gene indicates that 75.5-82.6% of mutations are silent and that 93.4% of amino acids are conserved in the four FMDV replicases. The frequency of certain types of silent mutations and of rare codon usage is significantly lower for the replicase gene than for the protein VP1 coding region.

Amino Acid Sequence↗
PubMed1987

A quantitative model of myosin phosphorylation and the photomechanical response of the isolated sphincter pupillae of the frog iris.

The time courses of isometrically recorded photomechanical responses of isolated sphincter pupillae of Rana pipiens can be accurately predicted by a set of differential equations derived from phosphorylation theory of smooth muscle contraction. We compared actual light-stimulated contractions with calculated ones over a wide range of stimulus intensities (56-fold) and durations (0.4-4.0 s). The hypothetical Ca++-calmodulin-myosin light chain kinase cascade acts as a "valve" to control the flow of ATP through a phosphorylation-dephosphorylation cycle. When the rate of flow of ATP through the phosphorylation-dephosphorylation cycle is increased, the percentage of phosphorylated myosin increases. The time courses of the concentrations of phosphorylated myosin during different responses are seen to be functions of the time courses of the opening and closing of the coupling cascade "valve." The calculations predict experimentally measurable intermediate variables, which can aid the investigation of the application of quantitative phosphorylation theory to amphibian sphincter pupillae and to smooth muscle in general.

Adenosine Triphosphate↗
PubMed2002

Adverse childhood experiences and risk of paternity in teen pregnancy.

OBJECTIVE: Few studies have investigated risk factors that predispose males to be involved in teen pregnancies. To provide new information on such factors, we examined the relationships of eight common adverse childhood experiences to a male's risk of impregnating a teenager. METHODS: We conducted a retrospective cohort study using questionnaire responses from 7399 men who visited a primary care clinic of a large health maintenance organization in California. Data included age of the youngest female ever impregnated; the man's own age at the time; his history of childhood emotional, physical, or sexual abuse; having a battered mother; parental separation or divorce; and having household members who were substance abusers, mentally ill, or criminals. Odds ratios (ORs) for the risk of involvement in a teen pregnancy were adjusted for age, race, and education. RESULTS: At least one adverse childhood experience was reported by 63% of participants, and 34% had at least two adverse childhood experiences; 19% of men had been involved in a teen pregnancy. Each adverse childhood experience was positively associated with impregnating a teenager, with ORs ranging from 1.2 (sexual abuse) to 1.8 (criminal in home). We found strong graded relationships (P <.001) between the number of adverse childhood experiences and the risk of involvement in a teen pregnancy for each of four birth cohorts during the last century. Compared with males with no adverse childhood experiences, a male with at least five adverse childhood experiences had an OR of 2.6 (95% confidence interval [CI] 2.0, 3.4) for impregnating a teenager. The magnitude of the ORs for the adverse childhood experiences was reduced 64-100% by adjustment for potential intermediate variables (age at first intercourse, number of sexual partners, having a sexually transmitted disease, and alcohol or drug abuse) that also exhibited a strong graded relationship to adverse childhood experiences. CONCLUSION: Adverse childhood experiences have an important relationship to male involvement in teen pregnancy. This relationship has persisted throughout four successive birth cohorts dating back to 1900-1929, suggesting that the effects of adverse childhood experiences transcend changing sexual mores and contraceptive methods. Efforts to prevent teen pregnancy will likely benefit from preventing adverse childhood experiences and their associated effects on male behaviors that might mediate the increased risk of teen pregnancy.

Adolescent↗
PubMed2002

Quantitative computed tomography estimates of the mechanical properties of human vertebral trabecular bone.

The objective of this study was to report our quantitative computed tomography (QCT) density-mechanical property regressions for trabecular bone for use in biomechanical modelling of the human spine. Cylindrical specimens of human vertebral trabecular bone (from T10 to L4) were cored from 32 cadavers (mean +/- SD age = 70.1 +/- 16.8; 13 females, 19 males) and scanned using QCT. Mechanical tests were conducted using a protocol that minimized end-artifacts over the apparent density range tested (0.09-0.38 g/cm3). To account for the presence of multiple specimens per donor in this data set, donor was treated as a random effect in the regression model. Mean modulus (319 +/- 189 MPa) was higher and mean yield strain (0.78 +/- 0.06%) was lower than typical values reported previously due to minimization of the end-artifact errors. QCT density showed a strong positive correlation with modulus (n = 76) and yield stress (r2 = 0.90-0.95, n = 53, p < 0.001). There was a weak positive linear correlation with yield strain (r2 = 0.58, n = 53, p = 0.07). Prediction errors, incurred when estimating modulus or strength for specimens from a new donor, were 30-36% of the mean values of these properties. Direct QCT density-mechanical property regressions gave more precise predictions of mechanical properties than if physically measured wet apparent density was used as an intermediate variable to predict mechanical properties from QCT density. Use of these QCT density-mechanical property regressions should improve the fidelity of QCT-based biomechanical models of the human spine for whole bone and bone-implant analyses.

Adult↗
PubMed2003

Validation of flow cytometry to quantify the potency of anti-D immunoglobulin preparations.

BACKGROUND AND OBJECTIVES: Flow cytometry has been recommended as an alternative to that of autoanalyser methodology for estimation of anti-D potency. This investigation was performed to validate the flow cytometry method based on a quality assurance system. MATERIALS AND METHODS: A flow cytometry method based on indirect labelling of Rh(D)-positive red blood cells was validated using the parameters precision and accuracy and was compared to the autoanalyser data of manufacturers of anti-D immunoglobulin preparations. RESULTS: The experiment first investigated the possible differences between assays from single donors compared with a pooled assay. Red blood cells of four individual donors and their pooled red blood cells were interchangeable. There was no significant difference between donors, on one hand, and between the use of a single donation and the pooled red blood cells, on the other hand (P = 0.695). The two-sided 95% confidence intervals (CIs) of the difference between single donors and the pool ranged from -4.6% to 4.7%. The intermediate variability was determined by standard deviation (SD) = 48.4 IU/ml [coefficient of variation (CV) = 3.8%]; the repeatability was SD = 34.3 IU/ml (CV = 2.7%). Using a spiking experiment, the second part of the experiment investigated recovery of a known anti-D potency. The recovery of samples spiked with defined amounts of reference preparation was 97.7-101%, with a mean bias of -1.3 (95% CI: -4.1 to 1.6). The results of the flow cytometry assay, as compared to those of the autoanalyser performed by the manufacturers of anti-D immunoglobulin preparations for those manufacturers who have their method validated in-house, ranged from 87 to 129%, indicating good correlation. CONCLUSIONS: Flow cytometry is a suitable quality control method for polyclonal anti-D immunoglobulins, which can be standardized in a quality control laboratory using a quality assurance system.

Automation↗
PubMed2001

Multidimensional epistasis and the disadvantage of sex.

Sex is thought to facilitate accumulation of initially rare beneficial mutations by allowing simultaneous allele replacements at many loci. However, this advantage of sex depends on a restrictive assumption that the fitness of a genotype is determined by fitness potential, a single intermediate variable to which all loci contribute additively, so that new alleles can accumulate in any order. Individual-based simulations of sexual and asexual populations reveal that under generic selection, sex often retards adaptive evolution. When new alleles are beneficial only if they accumulate in a prescribed order, a sexual population may evolve two or more times slower than an asexual population because only asexual reproduction allows some overlap of successive allele replacements. Many other fitness surfaces lead to an even greater disadvantage of sex. Thus, either sex exists in spite of its impact on the rate of adaptive allele replacements, or natural fitness surfaces have rather specific properties, at least at the scale of intrapopulation genetic variability.

Adaptation, Physiological↗
PubMed2002

Life cycle variation of Myzus persicae (Hemiptera: Aphididae) in Greece.

During the years 1995-1999 the life cycle category of 2797 clones of Myzus persicae (Sulzer) was examined. The clones originated from primary and secondary hosts from different localities of North and Central Greece and the island of Crete in the south. Four different overwintering life cycle strategies were found that have also been described for M. persicae and other heteroecious species previously. A geographical variation was found in the proportion of holocyclic clones from tobacco and other secondary hosts associated with the abundance of the primary host in the sampling regions. In Central Macedonia, around the main peach-growing regions, the proportion of holocyclic clones was mostly above 50% and in some cases reached 100%. In localities of East Macedonia, holocyclic clones were also frequent. On the other hand, further south or in north-eastern Greece, where peach is not common, the proportion of holocyclic clones varied between 0 and 33%. Fifty seven percent of examined anholocyclic clones produced males under short day conditions, suggesting that androcyclic clones in Greece represent an important factor of genetic variability. Intermediate clones were sampled from all host-plants but at low frequencies (3.6% of total examined clones and 6.9% of non-holocyclic ones). Moreover, a regional variation was found in different colour forms feeding on tobacco plants. Red clones were predominant in regions where aphids overwinter parthenogenetically on weeds or winter crops. However, almost all clones from the primary host were green. The ecological aspects of life cycle variation are discussed.

Animals↗
PubMed1987

Bone dynamics: stress, strain and fracture.

Bone is a dynamic tissue whose functional mass is controlled by the balance between the endocrine drive towards bone resorption and the mechanically-engendered drive towards bone formation. Strain is the key intermediate variable between loading forces and bone remodelling. Animal studies have shown that static loading of bone has no osteogenic effect; bone loss occurs as if there were no loading at all. However, dynamic loading, that is, cyclic change in internal strain, is strongly osteogenic, with relatively few cycles required for maximum effect. However, if a sufficient number of cycles is applied, repetitive loading can cause stress fractures. This number decreases as internal strains increase. Thus strain redistribution within bone, as caused by muscle fatigue or improper sports equipment, is a significant cause of fracture.

Aging↗
PubMed1973

Cell contacts in the mouse mammary gland. I. Normal gland in postnatal development and the secretory cycle.

The nature and distribution of cell contacts have been examined in thin sections and freeze-fracture replicas of mammary gland samples from female C3H/Crgl mice at stages from birth through pregnancy, lactation, and postweaning involution. Epithelial cells of major mammary ducts at all stages examined are linked at their luminal borders by junctional complexes consisting of tight junctions, variable intermediate junctions, occasional small gap junctions, and one or more series of desmosomes. Scattered desmosomes and gap junctions link ductal epithelial and myoepithelial cells in all combinations; hemidesmosomes attach myoepithelial cells to the basal lamina. Freeze-fracture replicas confirm the erratic distribution of gap junctions and reveal a loose, irregular network of ridges comprising the continuous tight-junctional belts. Alveoli develop early in gestation and initially resemble ducts. Later, as alveoli and small ducts become actively secretory, they lose all desmosomes and most intermediate junctions, whereas tight and gap junctions persist, The tight-junctional network becomes compact and orderly, its undulating ridges oriented predominantly parallel to the luminal surface. It is suggested that these changes in junctional morphology, occurring in secretory cells around parturition, may be related to the greatly enhanced rate of movement of milk precursors and products through the lactating epithelium, or to the profound and recurrent changes in shape of secretory cells that occur in relation to myoepithelial cell contraction, or to both.

Animals↗
PubMed2002

Use of a marginal structural model to determine the effect of aspirin on cardiovascular mortality in the Physicians' Health Study.

The 1982-1988 aspirin component of the Physicians' Health Study, a randomized trial of aspirin and beta-carotene in primary prevention of cardiovascular disease and cancer among 22,071 US male physicians, was terminated early primarily because of a statistically extreme 44% reduction in first myocardial infarction, with inadequate precision and no apparent effect on the primary endpoint, cardiovascular death. Because of the demonstrated efficacy of aspirin in secondary prevention of cardiovascular death, nonfatal cardiovascular events may simultaneously be time-dependent confounders and intermediate variables. Aspirin use is strongly influenced by these as well as other diseases, side effects, and cardiovascular risk factors. The authors used a marginal structural model with time-dependent inverse probability weights to estimate the underlying causal effect of aspirin on cardiovascular mortality. Although intention-to-treat analyses found no effect (rate ratio = 1.00, 95% confidence interval (CI): 0.72, 1.38), the estimated causal rate ratio was altered to 0.75 but remained nonsignificant (95% CI: 0.48, 1.16). As-treated analyses suggested a more modest effect of aspirin use (rate ratio = 0.90, 95% CI: 0.65, 1.25). Although the numbers of cardiovascular deaths were insufficient to evaluate this endpoint definitively, use of such methods holds much potential for controlling time-varying confounders affected by previous exposure.

Adult↗
PubMed2002

All-cause and cause-specific death rates by educational status for two million people in two American Cancer Society cohorts, 1959-1996.

Low socioeconomic status is associated with high mortality, but the extent to which socioeconomic status affects particular diseases and whether socioeconomic status effects have changed over time are uncertain. The authors used education as a marker for socioeconomic status in a study of two large American Cancer Society cohorts (follow-up, 1959-1996). Low education was associated with higher death rates in both cohorts from all causes and most specific causes, except breast cancer and external causes among women. Life expectancy in the more recent cohort was 4.8 years shorter for men and 2.7 years shorter for women for the least versus the most educated. The inverse relation between education and mortality was strongest for coronary heart disease, lung cancer, diabetes, and chronic obstructive pulmonary disease; moderate for colorectal cancer, external causes (men only), and stroke; weak for prostate cancer; and reversed for external causes among women. The direction of a weak gradient for breast cancer differed for those with and without prevalent breast cancer at baseline. Adjustment for conventional risk factors, probable intermediate variables between education and mortality, diminished but did not eliminate the observed educational/mortality gradients. Temporal trends showed increasing mortality differences by education for coronary heart disease, diabetes, and lung cancer for women.

Adult↗
PubMed2003

Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models.

To estimate the net (i.e., overall) effect of highly active antiretroviral therapy (HAART) on time to acquired immunodeficiency syndrome (AIDS) or death, the authors used inverse probability-of-treatment weighted estimation of a marginal structural model, which can appropriately adjust for time-varying confounders affected by prior treatment or exposure. Human immunodeficiency virus (HIV)-positive men and women (n = 1,498) were followed in two ongoing cohort studies between 1995 and 2002. Sixty-one percent (n = 918) of the participants initiated HAART during 6,763 person-years of follow-up, and 382 developed AIDS or died. Strong confounding by indication for HAART was apparent; the unadjusted hazard ratio for AIDS or death was 0.98. The hazard ratio from a standard time-dependent Cox model that included time-varying CD4 cell count, HIV RNA level, and other time-varying and fixed covariates as regressors was 0.81 (95% confidence interval: 0.61, 1.07). In contrast, the hazard ratio from a marginal structural survival model was 0.54 (robust 95% confidence interval: 0.38, 0.78), suggesting a clinically meaningful net benefit of HAART. Standard Cox analysis failed to detect a clear net benefit, because it does not appropriately adjust for time-dependent covariates, such as HIV RNA level and CD4 cell count, that are simultaneously confounders and intermediate variables.

Acquired Immunodeficiency Syndrome↗
PubMed1992

G-estimation of the effect of prophylaxis therapy for Pneumocystis carinii pneumonia on the survival of AIDS patients.

AIDS Clinical Trial Group Randomized Trial 002 compared the effect of high-dose with low-dose 3-azido-3-deoxythymidine (AZT) on the survival of AIDS patients. Embedded within the trial was an essentially uncontrolled observational study of the effect of prophylaxis therapy for pneumocystis carinii pneumonia on survival. In this paper, we estimate the causal effect of prophylaxis therapy on survival by using the method of G-estimation to estimate the parameters of a structural nested failure time model (SNFTM). Our SNFTM relates a subject's observed time of death and observed prophylaxis history to the time the subject would have died if, possibly contrary to fact, prophylaxis therapy had been withheld. We find that, under our assumptions, the data are consistent with prophylaxis therapy increasing survival by 16% or decreasing survival by 18% at the alpha = 0.05 level. The analytic approach proposed in this paper will be necessary to control bias in any epidemiologic study in which there exists a time-dependent risk factor for death, such as pneumocystis carinii pneumonia history, that (A1) influences subsequent exposure to the agent under study, for example, prophylaxis therapy, and (A2) is itself influenced by past exposure to the study agent. Conditions A1 and A2 will be true whenever there exists a time-dependent risk factor that is simultaneously a confounder and an intermediate variable.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Coronary heart disease risk reduction in a predominantly beer-drinking population.

Moderate alcohol consumption protects against coronary heart disease, but there is ongoing debate about whether the effects and the underlying mechanisms differ by type of alcoholic beverage. In our case-control study from Germany, we assessed and compared the effect of alcohol consumption from various sources on risk of coronary heart disease and its underlying mechanisms. The sample included 312 patients with clinically stable, angiographically confirmed coronary heart disease and 479 healthy controls. After control for potential confounding factors, the odds ratio for coronary heart disease was 0.55 (95% confidence interval = 0.37--0.83) for drinkers compared with nondrinkers. Risk reduction was particularly strong among the majority of study participants who reported drinking predominantly or exclusively beer. Alcohol consumption from various sources was consistently associated with a more favorable profile of lipids and hemostatic factors. Nevertheless, a strong inverse association persisted between beer drinking and coronary heart disease even after control for these "intermediate variables." Our results support suggestions that the protective effect of moderate alcohol consumption against coronary heart disease is mediated in part by beneficial effects of ethanol on lipids and hemostatic factors. Additional mechanisms may account for the strong protective effect of moderate beer consumption.

Adult↗
PubMed1999

The graft versus leukemia effect after bone marrow transplantation: a case study using structural nested failure time models.

Over the last decade, J. M. Robins has developed a set of tools for assessing, from observational data, the causal effects of a time-dependent treatment or exposure in the presence of time-dependent covariates that may be simultaneously confounders and intermediate variables. This report concerns a case study of the application of one these techniques, G-estimation using structural nested failure time models, to the problem of assessing the effect of graft versus host disease on leukemia relapse after bone marrow transplantation.

Biometry↗