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PubMed2006

Factors associated with the effect-size of thiazolidinedione (TZD) therapy on HbA(1c): a meta-analysis of published randomized clinical trials.

OBJECTIVE: To examine factors affecting the size of the HbA(1c) response to thiazolidinedione (TZD) therapy. RESEARCH DESIGN AND METHODS: Meta-analysis of randomized TZD controlled trials which were identified using PubMed, EBSCO and Sci-lit databases and were published in English. Sociodemographic and clinical data were extracted from each trial. HbA(1c) effect size was defined as either a placebo-subtracted change in HbA(1c) or a change in HbA(1c) from baseline. Weighted multivariable regression was used to examine factors associated with changes in HbA(1c). Bootstrapped smearing estimates were computed to obtain reliable estimates of HbA(1c) effect size. RESULTS: Forty-two trials yielded 60 trial arms which represented 8322 patients treated with thiazolidinediones. Weighted placebo-subtracted change in HbA(1c) was -0.99% +/- 0.02% with an average baseline HbA(1c) of 9.1% +/- 1.0%. Weighted bootstrapped smearing estimate of the placebo-subtracted change in HbA(1c) was -1.02% +/- 0.004%. After controlling for other variables, the baseline HbA(1c) level had a significant negative association with placebo-subtracted HbA(1c) change (p = 0.004) and also with change in HbA(1c) from baseline (p = 0.002). Longer trial duration was associated with greater placebo-subtracted HbA(1c) change (p = 0.01) but not with the change in HbA(1c) from baseline. The multivariable models explained 72% of the variation in placebo-subtracted HbA(1c) change. It was not possible to estimate effects of the run-in period and obesity on TZD effect size. CONCLUSION: Baseline HbA(1c) and trial duration significantly impacted the effect size of TZD therapy on HbA(1c). Age, gender, duration of diabetes and prior use of anti-diabetic therapy were not associated with the TZD effect size.

Diabetes Mellitus↗

PubMed2005

The therapeutic effect of clinical trials: understanding placebo response rates in clinical trials--a secondary analysis.

BACKGROUND AND PURPOSE: Placebo response rates in clinical trials vary considerably and are observed frequently. For new drugs it can be difficult to prove effectiveness superior to placebo. It is unclear what contributes to improvement in the placebo groups. We wanted to clarify, what elements of clinical trials determine placebo variability. METHODS: We analysed a representative sample of 141 published long-term trials (randomized, double-blind, placebo-controlled; duration > 12 weeks) to find out what study characteristics predict placebo response rates in various diseases. Correlational and regression analyses with study characteristics and placebo response rates were carried out. RESULTS: We found a high and significant correlation between placebo and treatment response rate across diseases (r = .78; p < .001). A multiple regression model explained 79% of the variance in placebo variability (F = 59.7; p < 0.0001). Significant predictors are, among others, the duration of the study (beta = .31), the quality of the study (beta = .18), the fact whether a study is a prevention trial (beta = .44), whether dropouts have been documented (beta = -.20), or whether additional treatments have been documented (beta = -.17). Healing rates with placebo are lower in the following diagnoses; neoplasms (beta = -.21), nervous diseases (beta = -.10), substance abuse (beta = -.14). Without prevention trials the amount of variance explained is 42%. CONCLUSION: Medication response rates and placebo response rates in clinical trials are highly correlated. Trial characteristics can explain some portion of the variance in placebo healing rates in RCTs. Placebo response in trials is only partially due to methodological artefacts and only partially dependent on the diagnoses treated.

Data Interpretation, Statistical↗

PubMed2005

Optimal fetal growth for the Caucasian singleton and assessment of appropriateness of fetal growth: an analysis of a total population perinatal database.

BACKGROUND: The appropriateness of an individual's intra uterine growth is now considered an important determinant of both short and long term outcomes, yet currently used measures have several shortcomings. This study demonstrates a method of assessing appropriateness of intrauterine growth based on the estimation of each individual's optimal newborn dimensions from routinely available perinatal data. Appropriateness of growth can then be inferred from the ratio of the value of the observed dimension to that of the optimal dimension. METHODS: Fractional polynomial regression models including terms for non-pathological determinants of fetal size (gestational duration, fetal gender and maternal height, age and parity) were used to predict birth weight, birth length and head circumference from a population without any major risk factors for sub-optimal intra-uterine growth. This population was selected from a total population of all singleton, Caucasian births in Western Australia 1998-2002. Births were excluded if the pregnancy was exposed to factors known to influence fetal growth pathologically. The values predicted by these models were treated as the optimal values, given infant gender, gestational age, maternal height, parity, and age. RESULTS: The selected sample (N = 62,746) comprised 60.5% of the total Caucasian singleton birth cohort. Equations are presented that predict optimal birth weight, birth length and head circumference given gestational duration, fetal gender, maternal height, age and parity. The best fitting models explained 40.5% of variance for birth weight, 32.2% for birth length, and 25.2% for head circumference at birth. CONCLUSION: Proportion of optimal birth weight (length or head circumference) provides a method of assessing appropriateness of intrauterine growth that is less dependent on the health of the reference population or the quality of their morphometric data than is percentile position on a birth weight distribution.

Anthropometry↗

PubMedDate not supplied

Quality of life after radical prostatectomy.

PURPOSE/OBJECTIVES: To examine physical and psychosocial factors that affect the quality of life (QOL) for men 12-24 months after radical prostatectomy treatment for prostate cancer. DESIGN: Cross-sectional survey. SETTING: An entire population from one tumor registry. SAMPLE: Of the 132 men meeting inclusion criteria, 97 men responded, with 91 meeting analysis requirements. Analysis was completed on the Caucasian sample (n = 88) with a mean age of 66 years. Most men were married, lived with a spouse or partner, and had a high level of education. METHODS: A survey was developed to assess men 12-24 months prostatectomy. The tumor registry mailed the survey, which was completed at home, and participants returned it in a prestamped, addressed envelope. MAIN RESEARCH VARIABLES: Major hypotheses in the causal model were that age, sexual function, urinary function, and sexual appraisal would only have indirect effects on QOL, whereas urinary function appraisal, self-esteem, anger suppression, perceived social support, depression, and health locus of control would directly affect QOL. FINDINGS: As analyzed by path analytic techniques, the hypothesized causal model explained 72% variance in the QOL variable. Perceived social support, self-esteem, and health locus of control were significant predictors of QOL. Urinary function appraisal contributed indirectly through health locus of control. Contrary to the hypotheses, anger suppression and depression were not significant predictors of QOL. CONCLUSIONS: After radical prostatectomy for prostate cancer, perceived social support, self-esteem, and health locus of control may influence men's QOL. Future research is needed to increase understanding about the adaptation trajectory of men's response to the impact of prostate cancer. IMPLICATIONS FOR NURSING: Nurses can help patients by providing a thorough assessment of each patient's values that may affect QOL before any intervention begins, using research-based evidence regarding potential side effects of interventions, clear and concise information from a variety of sources that addresses the possible concerns of men and their spouses, and focused counseling that addresses patient-specific problems.

Adult↗

PubMed2005

Barriers to success for an evidence-based guideline for chronic obstructive pulmonary disease.

OBJECTIVES: To evaluate 1) barriers to clinical guideline use and 2) the relationship between guideline use and inpatient outcomes in chronic obstructive pulmonary disease (COPD). METHODS: 1) Four focus groups of specific health professions (n = 30), from three metropolitan hospitals, and interview of 99 medical officers (MOs), linked to 349 admissions, both guided by behavioural modelling theory; 2) association between guideline use and patient outcomes (length of hospital stay > or = 14 days, and readmission within 28 or 90 days) was evaluated in a cohort of 405 COPD patients. RESULTS: 1) In focus groups, nurses and allied health professionals emphasized facilitation issues including paperwork duplication and time limitations as barriers, but considered improved patient care outcomes as the major guideline use determinant. There were similar findings in junior MOs (nonconsultants) by both focus group and interview, with the addition of a need for a sense of ownership. Senior MOs (consultants) greatly emphasized sense of ownership. Barriers to guideline use varied between types of units. Behavioural modelling explained 49% of the variation in intention to use the guideline for MOs. For nonconsultants, habit and intention were significantly associated with extent of guideline use. 2) Patient outcomes: guideline use was not associated with length of stay or readmission. CONCLUSIONS: 1) Guideline implementation should address issues relevant to different health professions, units and seniority of profession. 2) Guideline use was not associated with reductions in readmission or length of stay.

Adult↗

PubMed2006

CARD15/NOD2 mutations in Crohn's disease.

Inflammatory bowel diseases (IBDs) are complex genetic disorders characterized by a complex interplay between genetic and environmental risk factors. At least ten genes or anonymous loci have been proposed to play a role in IBD. Among them, the best studied is CARD15/NOD2, a gene coding for a protein involved in bacterial recognition by cells involved in innate immunity. Despite a large amount of work, a consensus model explaining the effect of Card 15/NoD2 mutations did not emerge, and the disease mechanisms are still subject to debate.

Chromosome Mapping↗

PubMed1990

Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study.

The Goldie-Coldman model explaining the kinetics of tumor cell kill and drug resistance has a potential application in designing chemotherapy regimes. In this Southwest Oncology Group (SWOG) trial we tested the alternation of two potentially noncrossresistant drug combinations with a concurrent drug combination in patients with limited small-cell lung cancer. The concurrent drug combination consisted of etoposide (VP-16), 75 mg/m2/intravenously (IV), days 1, 2, and 3; vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), 40 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (EVAC). The alternating combination consisted of VP-16, 100 mg/m2/IV, days 1, 2, and 3; and cisplatin (CDDP), 100 mg/m2/IV, day 1, alternating with vincristine, 1.0 mg/m2/IV, days 1 and 8; Adriamycin, 50 mg/m2/IV, day 1; and cyclophosphamide, 750 mg/m2/IV, day 1 (VP-16/CDDP-VAC). Chemotherapy was administered at 3-week intervals for six cycles both before and after chest (5,000 rads/5 weeks) and whole brain radiotherapy (3,000 rads/2 weeks). One hundred ninety-nine patients received EVAC and 201 received the alternating combination. There was no significant difference in the response rate to the initial six cycles of treatment with EVAC (CR, 40%) versus the alternating combination (CR, 38%). There was no significant difference between the best response, EVAC (CR, 48%) and VP-16/CDDP-VAC (CR, 51%). Median survival for all randomized patients on EVAC is 15.1 months versus 16.5 months on the alternating combination (P = .58). Toxicities consisted primarily of bone marrow suppression, anorexia, nausea and vomiting, peripheral neuropathies, and alopecia. As in previous trials, the chest was the most common site of relapse (33%). There were no differences in the incidence and sites of relapse between the two treatment arms. These treatments appear equally effective at inducing remission and prolonging survival in patients with small-cell lung cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Decision making in pediatric oncology: who should take the lead? The decisional priority in pediatric oncology model.

Decision making in pediatric oncology can look different to the ethicist and the clinician. Popular ethical theories argue that clinicians should not make decisions for patients, but rather provide information so that patients can make their own decisions. However, this theory does not always reflect clinical reality. We present a new model of decision making that reconciles this apparent discrepancy. We first distinguish decisional priority from decisional authority. The person (parent, child, or clinician) who first identifies a preferred choice exercises decisional priority. In contrast, decisional authority is a nondelegable parental right and duty, in which a mature child may join. This distinction enables us to analyze decisional priority without diminishing parental authority. This model analyzes decisions according to two continuous underlying characteristics. One dominant characteristic is the likelihood of cure. Because cure, when possible, is the ultimate goal, the clinician is in a better position to assume decisional priority when a child probably can be cured. The second characteristic is whether there is more than one reasonable treatment option. The interaction of these two complex continual results in distinctive types of decisional situations. This model explains why clinicians sometimes justifiably assume decisional priority when there is one best medical choice. It also suggests that clinicians should particularly encourage parents (and children, when appropriate) to assume decisional priority when there are two or more clinically reasonable choices. In this circumstance, the family, with its deeper understanding of the child's nature and preferences, is better positioned to take the lead.

Child↗

PubMed2002

Social cognitive determinants of physical activity in young adults: a prospective structural equation analysis.

This study used a prospective design to test a model of the relation between social cognitive variables and physical activity in a sample of 277 university students. Social support, self-efficacy, outcome expectations, and self-regulation were measured at baseline and used to predict physical activity 8 weeks later. Results of structural equation modeling indicated a good fit of the social cognitive model to the data. Within the model, self-efficacy had the greatest total effect on physical activity, mediated largely by self-regulation, which directly predicted physical activity. Social support indirectly predicted physical activity through its effect on self-efficacy. Outcome expectations had a small total effect on physical activity, which did not reach significance. The social cognitive model explained 55% of the variance observed in physical activity.

Adolescent↗

PubMed1997

Glycemic control, self-care behaviors, and psychosocial factors among insulin treated diabetics: a test of an extended health belief model.

The relations of diet adherence (DA) and self-monitoring of blood glucose (SMBG) to metabolic control, as measured with glycosylated hemoglobin A(tc) (GHbA(tc), and correlates of self-care were examines among a type I diabetic sample (n = 423). The Health Belief Model (HBM), supplemented by other factors (locus of control, self-efficacy, health value, and social support), was used as a theoretical model. In multiple regression analyses both DA (p<.01) and SMBG (p<.001). SMBG showed strong associations with self-efficacy in SMBG (p,.001) and net benefits of SMBG (p<.001). The revised models explained 14% and 21% of the variation in DA and SMBG, respectively. The results suggest that although perceived net benefits are important determinants of both SMBG and DA, DA is also related to diabetes support, whereas SMBG is more strongly related to perceived self-efficacy. Thus self-care regimen should be planned individually for diabetic patients.

Journal Article↗

PubMed2000

The Xenopus tadpole gut: fate maps and morphogenetic movements.

We have produced a comprehensive fate map showing where the organs of the gut and respiratory system are derived from in the early Xenopus laevis endoderm. We also show the origin of the associated smooth muscle layer on a separate fate map. Comparison of the two maps shows that for most organs of the gut the prospective epithelium and smooth muscle do not overlie each other in the early embryo but come together at a later stage. These fate maps should be useful for future studies into endoderm specification. It was not previously known how the elongation of the endoderm occurs, how the single-layered dorsal and many-layered ventral endoderm gives rise to the single layered epithelium, and whether or not the archenteron cavity actually gives rise to the gut lumen. Using a variety of labelling procedures we show firstly, that radial intercalation occurs in the gut transforming a short thick tube into a long thin tube; secondly, that the archenteron lining does not become the definitive gut lumen. Instead the archenteron cavity almost closes at tailbud stages before providing a nucleus for the definitive gut cavity, which opens up during elongation. Based on this work we present a model explaining the morphogenesis of the gut.

Animals↗

PubMed2025

Origin and evolution of mitochondrial inner membrane composition.

Unique membrane architectures and lipid building blocks underlie the metabolic and non-metabolic functions of mitochondria. During eukaryogenesis, mitochondria likely arose from an alphaproteobacterial symbiont of an Asgard archaea-related host cell. Subsequently, mitochondria evolved inner membrane folds known as cristae alongside a specialized lipid composition supported by metabolic and transport machinery. Advancements in phylogenetic methods and genomic and metagenomic data have suggested potential origins for cristae-shaping protein complexes, such as the mitochondrial contact site and cristae-organizing system (MICOS). MICOS protein homologs function in the formation of cristae-like intracytoplasmic membranes (ICMs) in diverse extant alphaproteobacteria. The machinery responsible for synthesizing key mitochondrial phospholipids - which cooperate with cristae-shaping proteins to establish inner membrane architecture - could have also evolved from a bacterial ancestor, but its origins have been less explored. In this Review, we examine the current understanding of mitochondrial membrane evolution, highlighting distinctions between prokaryotic and eukaryotic mitochondrial-specific proteins and lipids and their differing roles in shaping cristae and ICM architecture, and propose a model explaining the concurrent specialization of the mitochondrial lipidome and inner membrane structure in eukaryogenesis. We discuss how advancements across a range of disciplines are shedding light on how multiple membrane components co-evolved to support the central functions of eukaryotic mitochondria.

Mitochondrial Membranes↗

PubMed1981

Development of the cell wall in Tetraselmis: role of the Golgi apparatus and extracellular wall assembly.

The green algal flagellate, Tetraselmis, is a key transition organism in the phylogeny of green algae. It has been proposed that the cell wall of Tetraselmis arose evolutionarily from the fusion of scales and that this event secondarily caused the alteration of some cytoplasmic processes such as mitotic and cytokinetic mechanisms. Ultrastructural and developmental studies of the cell wall were performed with several strains of Tetraselmis. Two major wall types are reported. The wall of type 1 cells consists of a thick inner region covered by a layer of regularly repeating subunits of 26 nm, comparable to the subunits found in the median W2-W6 layer of Chlamydomonas. The more elaborate type 2 cell wall consists of a thick median wall layer, homologous to the type 1 inner wall, with additional inner and outer strata of hairs, grains and scales. Development of the cell wall begins in the endomembrane system, particularly the Golgi apparatus, where fibrillar tufts and electron-dense droplets are synthesized, modified and transported to the outside. Here, the tufts and droplets are displaced around the protoplast and assemble in several steps to yield the intact wall. Edge-growth assembly of the wall occurs here synchronously with cytoplasmic developments to yield the characteristic anterior flagellar pit. Models explaining various aspects of this development are discussed. When released from the cell, the wall subunits are not completely comparable to stellate scales, but appear to correspond to developmental stages of scales in green flagellates possessing body scales.

Biological Evolution↗

PubMed1998

Relaxation and activation of graviresponses in Paramecium caudatum.

The kinetics of gravitaxis and gravikinesis in Paramecium caudatum were investigated by employing (1) step transitions from normal gravity (1 g) to weightlessness (microgravity) and (2) turns of the experimental chambers from the horizontal to the vertical position at 1 g. The transition to microgravity left existing cell orientations unchanged. Relaxation of negative gravitaxis under microgravity took longer than 10 s and may be described by the time constant of the decay of orientation coefficients. Gravitaxis was started at 1 g by turning the experimental chamber from a horizontal to a vertical position. Gravitaxis activated rapidly during the turning procedure and relaxed to an intermediate level after the turning had stopped. Gravity-induced regulation of swimming speed (gravikinesis) at 1 g had reached a steady state after 1 min; at this point, gravikinesis counteracted the effects of sedimentation (negative gravikinesis). A step transition to microgravity initially reversed the sign of the gravikinesis (positive gravikinesis). The relaxation of this kinetic response was not completed during 10 s of microgravity. The data suggest that gravikinesis is functionally unrelated to gravitaxis and is strongly affected by the rate of change in acceleration. We present a model explaining why gravikinesis reverses sign upon the onset of a step from 1 g to microgravity.

Animals↗

PubMed1999

Optimizing force and velocity: mandible muscle fibre attachments in ants

To be able to perform swift and powerful movements, ant mandible closer muscles are composed of two subpopulations of muscle fibres: fast fibres for rapid actions and slow fibres for forceful biting. All these fibres attach to a sturdy and complex apodeme which conveys force into the mandible base. Fast muscle fibres attach directly to the apodeme. Slow fibres may attach directly or insert at individual thin filament processes of the apodeme which vary in length. Comparisons of different ant species suggest two basic principles underlying the design of mandible muscles. (1) Ants specialized for fast mandible movements generally feature long heads which contain long fast muscle fibres that attach to the apodeme at small angles. Their muscles comprise only a few filament-attached fibres and they maximize speed of action at the expense of force output. (2) Ants performing particularly forceful mandible movements, such as seed cracking, rely on many short parallel muscle fibres contained within a broad head capsule. Their slower muscles incorporate a large proportion of filament-attached fibres. Two simple models explain how the attachment angles are optimized with respect to force and velocity output and how filament-attached fibres help to generate the largest power output from the available head capsule volume.

Journal Article↗

PubMed2002

Roughness-dependent friction force of the tarsal claw system in the beetle Pachnoda marginata (Coleoptera, Scarabaeidae).

This paper studies slide-resisting forces generated by claws in the free-walking beetle Pachnoda marginata (Coleoptera, Scarabaeoidea) with emphasis on the relationship between the dimension of the claw tip and the substrate texture. To evaluate the force range by which the claw can interact with a substrate, forces generated by the freely moving legs were measured using a load cell force transducer. To obtain information about material properties of the claw, its mechanical strength was tested in a fracture experiment, and the internal structure of the fractured claw material was studied by scanning electron microscopy. The bending stress of the claw was evaluated as 143.4-684.2 MPa, depending on the cross-section model selected. Data from these different approaches led us to propose a model explaining the saturation of friction force with increased texture roughness. The forces are determined by the relative size of the surface roughness R(a) (or an average particle diameter) and the diameter of the claw tip. When surface roughness is much bigger than the claw tip diameter, the beetle can grasp surface irregularities and generate a high degree of attachment due to mechanical interlocking with substrate texture. When R(a) is lower than or comparable to the claw tip diameter, the frictional properties of the contact between claw and substrate particles play a key role in the generation of the friction force.

Animals↗

PubMed2003

Functional characterization of bacterial signal peptide OmpA in a baculovirus-mediated expression system.

Signal sequences are evolutionarily conserved and are often functionally interchangeable between prokaryotes and eukaryotes. However, we have found that the bacterial signal peptide, OmpA, functions incompletely in insect cells. Upon baculovirus-mediated expression of chloramphenicol acetyltransferase (CAT) in insect cells, OmpA signal peptide led to the cytosolic accumulation of the CAT molecules in an aglycosylated, signal-peptide cleaved form, in addition to the secretion of the glycosylated CAT. When green fluorescent protein (GFP) was used as another reporter, the GFP molecules expressed from the OmpA-GFP construct was distributed primarily in the cytosol as aggresome-like structures. These results together suggest that, subsequent to the cleavage of OmpA signal peptide in the ER, some of the processed proteins are returned to the cytoplasm. Since the prototypical insect signal peptide, melittin, did not result in this ER-to-cytosol dislocation of the reporter proteins, we proposed a model explaining the dislocation process in insect cells, apparently selective to the OmpA-directed secretory pathway bypassing the co-translational transport.

Animals↗

PubMed2002

Factors associated with adherence to antiretroviral medication in HIV-infected patients.

The aim of the study was to assess adherence with antiretroviral medication in a sample of HIV patients in Hong Kong and identify predictors of adherence. The study used a cross-sectional correlational design. Adherence behaviour was assessed with the use of self-reports. Other scales assessed knowledge with HIV medication, coping, health locus of control, anxiety, depression and fatigue. A blood sample was also obtained to assess CD4+ counts and viral load. Sociodemographic characteristics and medical information were obtained from the medical records. A high adherence rate was found in this sample of 136 predominantly Chinese patients. There were only 13.7% of the patients being classified as non-adherent. Predictors of adherence included high self-efficacy in terms of being certain that the medication schedule will be followed all or most of the time as directed, low tension-anxiety scores, and low intensity of nausea and vomiting (R2=0.304). An expanded regression model revealed additional factors influencing adherence, including coping variables, pain and numbness in the hands and feet, age, disease stage, internal locus of control, fatigue, family support and taking medication twice daily. This model explained 49% of the variance in adherence. The results suggest that adherence is a multidimensional concept. Every effort should be made to assess in individuals those variables found to affect adherence and alter them whenever possible. Continuous support of patients and individualized medication programmes that will help patients adjust their treatment to their lifestyle are recommended.

Adaptation, Psychological↗