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Accuracy versus transparency in pharmacoeconomic modelling: finding the right balance.

As modellers push to make their models more accurate, the ability of others to understand the models can decrease, causing the models to lose transparency. When this type of conflict between accuracy and transparency occurs, the question arises, "Where do we want to operate on that spectrum?" This paper argues that in such cases we should give absolute priority to accuracy: push for whatever degree of accuracy is needed to answer the question being asked, try to maximise transparency within that constraint, and find other ways to replace what we wanted to get from transparency. There are several reasons. The fundamental purpose of a model is to help us get the right answer to a question and, by any measure, the expected value of a model is proportional to its accuracy. Ironically, we use transparency as a way to judge accuracy. But transparency is not a very powerful or useful way to do this. It rarely enables us to actually replicate the model's results and, even if we could, replication would not tell us the model's accuracy. Transparency rarely provides even face validity; from the content expert's perspective, the simplifications that modellers have to make usually raise more questions than they answer. Transparency does enable modellers to alert users to weaknesses in their models, but that can be achieved simply by listing the model's limitations and does not get us any closer to real accuracy. Sensitivity analysis tests the importance of uncertainty about the variables in a model, but does not tell us about the variables that were omitted or the structure of the model. What people really want to know is whether a model actually works. Transparency by itself can't answer this; only demonstrations that the model accurately calculates or predicts real events can. Rigorous simulations of clinical trials are a good place to start. This is the type of empirical validation we need to provide if the potential of mathematical models in pharmacoeconomics is to be fully achieved.

Economics, Pharmaceutical↗

Protein balance in the first week of life in ventilated neonates receiving parenteral nutrition.

BACKGROUND: Protein intake is frequently delayed in ill neonates because of concerns about their ability to metabolize substrates. OBJECTIVE: We aimed to determine the factors affecting protein balance in ventilated, parenterally fed newborns during the first week of life. DESIGN: Leucine kinetic studies were performed in 19 neonates by using the [1-(13)C]leucine tracer technique after 24 h of a stable total parenteral nutrition (TPN) regimen. TPN intakes were prescribed by rotating attending physicians, enabling assessment of protein metabolism over a range of clinically used nutrient intakes. RESULTS: Mean (+/-SD) birth weight was 1.497 +/- 0.779 kg, gestational age at birth was 30.3 +/- 4.0 wk, and age at study was 3.9 +/- 1.4 d. Amino acid intakes (AAIs) ranged from 0.0 to 2.9 g x kg(-1) x d(-1). Based on leucine kinetic data, protein balance was calculated as the difference between protein synthesis and catabolism. By multiple regression analysis, AAI was the only predictor associated independently with protein balance (P < 0.01); energy intake, lipid intake, glucose intake, birth weight, and gestational age were not. Both leucine oxidation and nonoxidative leucine disposal rates were significantly correlated with leucine intake (P < 0.0005 and P < 0.01, respectively). Of the 12 infants with AAIs > 1 g x kg(-1) x d(-1), only 1 infant was significantly catabolic (protein balance <-1 g x kg(-1) x d(-1)). There was no evidence of protein intolerance as determined by elevated creatinine (69 +/- 31 micromol/L), plasma urea nitrogen (6.7 +/- 2.53 mmol/L), or metabolic acidosis (pH: 7.36 +/- 0.05). CONCLUSIONS: Ill neonates can achieve a positive protein balance in the first days of life without laboratory evidence of protein toxicity.

Amino Acids↗

Sensory organization of balance responses in children 3-6 years of age: a normative study with diagnostic implications.

The effect of altered sensory environments on balance was studied in 82 healthy children between 3 and 6 years of age. The purpose was to obtain normative measurements of postural stability during early stages of development for use in clinical posturography. Subjects were tested in three visual conditions (eyes open, blind-folded, and sway-referenced visual enclosure) during stance on either a fixed or sway-referenced force platform (EquiTest). During sway-referenced conditions, spontaneous changes in the subject's center of force (COF) drove rotational displacements of the platform and/or visual surround. The gain of platform/COF or surround/COF displacement was altered from 0.00 to 1.5. An equilibrium score (ES) was calculated based on the amount of postural sway compared to the maximum sway possible without falling. A higher ES reflected greater postural stability. An improvement in postural stability was observed between 4 and 5 years of development when the sensory environment was fixed (sway referenced gain = 0.0). In a dynamic sensory environment, however, age-related improvements in postural stability were not uniform and depended upon the specific sensory condition. For example, while 6 year olds generally showed the greatest postural stability of any age group, all ages showed statistically equivalent equilibrium scores during stance on a compliant surface with eyes closed, at all sway gains. The ability to ignore misleading sensory inputs to maintain balance was observed at 3 years of age; 76% of the 3 year olds (n = 16) were able to maintain stance in altered sensory environments at the 1.0 sway gain. In addition, postural stability was greater when visual inputs were sway-referenced compared to conditions that manipulated the support surface compliance. These data suggest that the predominance of visual-vestibular control of balance gives way to a somatosensory-vestibular dependence by age 3, but that the transition to adult-like balance responses is not complete for all sensory conditions even by age 6. The use of posturography to enhance the assessment of pediatric vestibular and sensory integration deficits is discussed.

Age Factors↗

[Effects of a tilting training program on lower extremities function, depression, and self-efficacy among stroke inpatients].

PURPOSE: The purpose of this study was to identify effects of a tilting training program on lower extremities function, depression, and self-efficacy among stroke inpatients. METHOD: The subjects were 60 stroke patients hospitalized in an oriental medical hospital; 31 in the experimental group and 29 in the control group. A nonequivalent control group pretest-posttest design was used. The tilting training program consisted of 3 sessions and was implemented for 30 minutes daily during 3 weeks. Data was collected from Feb to July 2003, and analyzed by percentage, Fisher's exact probability, chi2-test, and t-test using the SPSS/Win 10.0 computerized program. RESULT: After treatment with the tilting training program, the experimental group was significantly increased in the mean score for function of lower extremities (t=2.72, p=.009) compared to the control group, especially for keeping standing balance (t=2.78, p=.007) and standing by oneself (t=3.32, p=.002). However, in the mean scores of depression and self-efficacy, there were no significant differences between the two groups. CONCLUSION: The tilting training program was effective for increasing the function of lower extremities and to improve walking ability earlier among stroke inpatients. Therefore, the tilting training program is applicable to increase the balance level in standing and walking ability at the early rehabilitation stage for stroke patients.

Adult↗

Motor learning and Parkinson disease: Refinement of movement velocity and endpoint excursion in a limits of stability balance task.

OBJECTIVE: To investigate the effects of practice on performance and retention of a balance task in persons with Parkinson disease (PD). METHODS: Ten persons with PD and 10 age and gender-matched healthy control subjects were tested on an anticipatory, static base of support, limits of stability (LOS) balance task on a force plate. The motor learning paradigm utilized for all subjects included an acquisition phase and retention tests at 24 h and 1 week after acquisition. A force plate was used for testing and to collect outcome measures including movement velocity (MVL), endpoint excursion (EPE), and directional control. Data were analyzed for differences between groups and change over time. RESULTS: Persons with PD demonstrated performance deficits relative to controls for MVL at all testing periods (P < 0.05), and initially for EPE (P < 0.05), but were able to maintain significant improvements through retention testing relative to baseline (P < 0.05). CONCLUSIONS: Persons with PD demonstrated unimpaired capacity for motor learning in a LOS balance task for MVL and EPE, although performance deficits remained for MVL. The results concur with previous motor learning research of upper extremity tasks by suggesting that individuals with mild to moderate PD exhibit a preserved ability to benefit from practice as a means of improving balance task performance.

Aged↗

Balance function and fall-related efficacy in patients with newly operated hip fracture.

OBJECTIVE: To investigate the relation between fall-related efficacy in daily-life activities and functional as well as instrumental tests of balance in patients with hip fracture. DESIGN: Analysis of different aspects of balance using the Falls Efficacy Scale, Swedish version FES(S), questions on fear of falling, Functional Reach (FR) and tests on a balance platform (Chattanooga). SUBJECTS: Fifty-five elderly inpatients (mean age 82.3) with newly operated hip fracture who were assessed during the last week in hospital before discharge. RESULTS: The results showed a significant relationship between the subjective ability measured with the FES(S) and the objectively measured balance in the Functional Reach test and also between fall-related efficacy measured with FES(S) and fear of falling. Very few significant correlations were found between the results from balance tests on the force platform and those obtained with FES(S) and FR. CONCLUSIONS: Both the Falls Efficacy Scale, Swedish version, and the Functional Reach have been shown to be useful in analysing balance function in elderly patients newly operated on for hip fracture. The Falls Efficacy Scale also indicates which of the daily activities the patient perceives as troublesome and thus require further training.

Accidental Falls↗

Importance of hydrophobic region in amphiphilic structures of alpha-helical peptides for their gene transfer-ability into cells.

It has been showned that cationic alpha-helical peptides can be useful as nucleic acid-carrier molecules for gene transfer into cells. In order to investigate the significancemake sure of importance of the hydrophobic region in amphiphilic peptides in relation to their transfection ability, we have employed five kinds of peptides with a systematically varied hydrophobic-hydrophilic balance in the amphiphilic structures, and have evaluated the relationship between the structure and the gene transfer ability of the peptides into COS-7 cells. The peptides with a large hydrophobic region took alpha-helical structures, formed large aggregates and showed high transfection efficiency. Their high efficiency can be explained on the basis of their ability to form stable aggregates which can be internalized by endocytosis and remain resistant to digestion in lysosomal vesicles. Furthermore, it was suggested that the hydrophobic region of peptides plays an important role in the disruption of the endosomal membrane, which ca prevent the degradation of DNA in lysosomal vesicles. When peptides do not have so strong membrane-disruptive activity, but form aggregates which can be incorporated by endocytosis, the transfection efficiency can be recovered by the addition of an endosome-disruptive peptide.

Amino Acid Sequence↗

Effects of age on balance assessment using voluntary and involuntary step tasks.

BACKGROUND: Taking a step while standing and modifying a step while walking are two strategies often used to maintain balance when balance disturbances are encountered during activities of daily living. This study investigated whether performance on an involuntary step task, which is assumed to be a surrogate for fall recovery abilities, was comparable to performance on a voluntary step task. METHODS: The performance of a voluntary and an involuntary step task was measured in healthy young adult (mean age 21 years) and healthy elderly adult (mean age 68 years) female subjects. Subjects stepped as fast as possible in the direction of a minimally destabilizing lateral waist pull (voluntary step task), or they responded naturally to a large destabilizing lateral waist pull (involuntary step task). The effects of age, task, and their interaction on the primary outcome variables of step foot liftoff time, landing time, step length, and step height were examined. RESULTS: In the voluntary step task, the older adults, compared to the young, required significantly more time to lift their foot (Young: 307 msec; Elderly: 424 msec). In the involuntary step task, the elderly were as quick as the young in lifting their foot (Young: 322 msec; Elderly: 335 msec). The young lifted their foot at about the same time for the two tasks. The elders, on the other hand, lifted their foot significantly earlier in the involuntary step task, compared to the voluntary step task (Vol: 424 msec; Invol: 335 msec). CONCLUSIONS: A voluntary step task underestimates the ability of healthy elderly adults to respond quickly when large destabilizing balance disturbances are encountered.

Accidental Falls↗

Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 1, 6, 8, 10, and 12.

A report on an initial genome screen on 540 individuals in 97 families was collected as part of the NIMH Genetics Initiative on Bipolar Disorder. Families were ascertained to be informative for genetic linkage and underwent a common ascertainment and assessment protocol at four clinical sites. The sample was genotyped for 65 highly polymorphic markers from chromosomes 1, 6, 8, 10, and 12. The average intermarker interval was 16 cM. Genotypic data was analyzed using affected sib pair, multipoint affected sib pair, and pedigree analysis methods. Multipoint methods gave lod scores of approximately two on chromosomes 1, 6, and 10. The peak lod score on chromosome 6 occurred at the end of the q-arm, at some distance from the 6p24-22 area previously implicated for schizophrenia. We are currently genotyping additional markers to reduce the intermarker interval around the signals. The interpretation of results from a genome screen of a complex disorder and the problem of achieving a balance between detecting false positive results and the ability to detect genes of modest effect are discussed.

Bipolar Disorder↗

High-dose rate intraoperative radiation therapy for pediatric solid tumors.

BACKGROUND: Sixteen pediatric patients with solid tumors received treatment on a protocol designed to test the feasibility and safety of high-dose rate intraoperative radiation therapy (IOHDR) via a remote afterloader. PATIENTS AND METHODS: Patients with Ewing's sarcoma (n = 5), rhabdomyosarcoma (n = 3), synovial cell sarcoma (n = 2), Wilms tumor (n = 2), osteosarcoma, immature teratoma, desmoplastic small round cell tumor, and inflammatory fibrosclerosis were included. IOHDR was used in the initial management of nine patients and at the time of recurrence in seven. Indications for treatment included gross residual disease in 5 and suspected microscopic disease in 11. The general sites treated were the abdomen (n = 3), chest-wall/thoracic cavity (n = 7), and pelvis (n = 6). All of the patients received multiagent chemotherapy prior to the IOHDR procedure, and 5 had been previously treated with external beam radiation therapy. Separate from the procedure during which IORT was performed, 9 patients underwent an attempt at resection at the time of their initial presentation. A dose of 1200 cGy was prescribed to a depth of 0.5 cm from the surface of a multichannel tissue-equivalent applicator. Complications ascribed to IOHDR included an abscess, delayed wound healing, and cytopenia. Four patients received supplemental external beam radiation therapy to the IOHDR site. At the time of IOHDR, 3 patients had disseminated disease within the pleural cavity and one had pulmonary metastases. RESULTS: With a median follow-up of 18 months, the actuarial rates of local control, metastasis-free, and overall survival at 2 years were 61%, 51%, and 54%, respectively. The patterns of failure were local (n = 1), distant (n = 1), and local + distant (n = 1). Two patients are alive with active disease. Nine are alive with no evidence of disease and the remaining 5 are dead from disease (n = 2), other causes (n = 1), or treatment (n = 2). CONCLUSIONS: The potential to improve local control with high doses of radiation should be balanced against the risk of late effects. The ability to confine the dose of radiation to the primary site and decrease the dose to normal tissues makes IOHDR an important adjunct to external beam radiation therapy. IOHDR can be a safe and integral component in the management of pediatric solid tumors.

Child↗

Subchondral bone and cartilage repair with bioactive glasses, hydroxyapatite, and hydroxyapatite-glass composite.

The repair of an osteochondral defect in rabbit femur was studied with three kinds of bioactive glasses (BG), hydroxyapatite (HA), and hydroxyapatite-glass (HAG) composite. Seventy-two osteochondral defects were created in 18 rabbits. Sixty-four cylinders were implanted and eight defects were left empty as controls. Histomorphometry, scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDXA) were used for evaluation. Small osteochondral defects in rabbit femur found to heal themselves by regeneration. The three BGs, HA, and HAG led to direct lamellar bone repair of subchondral bone and restoration of articular surfaces mostly with hyalinelike cartilage in 12 weeks. However, the composition of the materials affects their behavior. Chondrogenesis took place earlier with the BGs than with HA. HAG degraded too much, glass 14 was too reactive and brittle, and the high alumina content in glass 11 disturbed its bone-bonding ability. Glass 7 and HA were the most balanced in the repair process. A special preparation method was used to retain soft tissues fairly unchanged and enable them to the observed together with hard tissues in SEM analysis.

Animals↗

Motor response to levodopa and the evolution of motor fluctuations in the first decade of treatment of Parkinson's disease.

Thirty-four patients with Parkinson's disease were followed for a mean period of 8 years from the time of initiation of levodopa medication. Levodopa response was charted from the starting point of pharmacological treatment to give a longitudinal point of view of the changes that evolve as the disease progresses. Objective measurements of the motor response to levodopa test-doses were made at approximately three yearly intervals. Motor fluctuations developed in 58% of the patient group after a mean treatment period of 35 months. Dyskinesia developed in parallel with fluctuations but appeared on average 7 months before symptomatic wearing-off effects of levodopa doses. The patients with motor fluctuations had significantly better responses to levodopa. By contrast, nonfluctuators were more prone to develop increasing midline motor disability affecting speech, gait and balance. Comparison of test-dose and pretreatment scores suggested that a substantial long-duration response to levodopa remains after many years of treatment, and that lateralized motor deficits show a stronger long duration response than midline ones. Motor fluctuations are a consequence of disease progression but their early development is, on balance, associated with better long-term functional ability because these patients have the greater capacity to respond to pharmacological treatment.

Adult↗

Modulation of intracellular second messengers by dietary fat during colonic tumor development.

In conclusion, dietary n-3 polyunsaturated fatty acids found in fish oil are capable of suppressing carcinogen-induced ras activation in the colon prior to overt neoplasia. This in turn blocks the oncogene driven increase in colonic diacylglycerol mass, preventing the persistent activation and chronic down-regulation of PKC isozymes, thereby maintaining tissue PKC levels. Since the maintenance of crypt PKC levels may sustain the homeostatic balance between cell proliferation, differentiation and apoptosis, the ability of dietary n-3 polyunsaturated fatty acids to block the carcinogen-induced decrease in steady-state levels of colonic mucosal PKC may in part explain why these fatty acids protect against colon tumorigenesis. Additional studies are required in order to elucidate the mechanisms by which select dietary lipids reduce colonic tumor incidence. This research focus is absolutely essential, because if we do not know why a dietary component is protective or promotive of cancer, then we have no right to attempt to modify eating behaviors.

Animals↗

Factors influencing immune complex localisation.

In systemic immune complex (IC) diseases such as SLE and rheumatoid vasculitis, IC accumulate in a number of tissues, either after deposition from the circulation or from in situ formation. The tissue localisation of IC depends on a delicate balance between the production of IC and the ability of the mononuclear phagocytic system (MPS) to remove them from blood. At times IC are cleared inefficiently, persist in the circulation and subsequently localise in tissues. This review evaluates the role of local tissue factors - anatomical, physiological, physical and immunological - in this process. We report on our studies examining the significance of C3b and IgG Fc receptors in tissues subject to IC deposition. No evidence for such receptors was found with the exception of a C3b receptor in human glomeruli. Our negative findings may be due to methodological difficulties in the identification of in situ receptors. Alternatively, immune receptors may not be present at these extra-glomerular sites and would therefore be unlikely to participate in IC localisation.

Animals↗

Cancer surveillance and information: balancing public health with privacy and confidentiality concerns (United States).

Rapid advances in informatics and communication technologies are greatly expanding the capacity for information capture and transportation. While these tools can be used for great good, they also offer new opportunities for those who seek to obtain and use information for improper purposes. While issues related to identity theft for financial gain garner the most attention, protection of privacy in public health endeavors such as cancer surveillance is also a significant concern. Some efforts to protect health-related information have had unintended consequences detrimental to health research and public health practice. Achieving a proper balance between measures to protect privacy and the ability to guard and improve public health requires careful consideration and development of appropriate policies, regulations and use of technology.

Confidentiality↗

Fourier transform infrared and differential scanning calorimetric studies of a surface-active material from rabbit lung.

A surface-active material with a chemical composition consistent with lung surfactant and with the ability to lower surface tension on a Wilhelmy balance to about 6 mN/m, has been isolated from rabbit pulmonary lavage. The thermotropic properties have been characterized with the techniques of Fourier transform infrared spectroscopy (FT-IR) and Differential Scanning Calorimetry (DSC). FT-IR melting curves were constructed from the temperature-dependence of the lipid CH2 symmetric stretching vibrational frequencies near 2850 cm-1. A broad gel-liquid crystal phase transition with an onset temperature of about 22 degrees C, and a completion temperature of about 38 degrees C was observed, with slight sample-to-sample variations in temperatures. A similar completion temperature was noted in DSC endotherms. Ca2+ (5-10 mM) increased the onset temperature of the lipid-melting event, and induced an ordering of surfactant and of its lipid extract at all temperatures studied. The effect on the lipids was suggestive of a Ca2+-induced phase separation caused by ion binding to phosphatidylglycerol and other acidic components. Evidence for a direct interaction between Ca2+ and the phosphate groups was suggested through small Ca2+-induced shifts in the 1090 cm-1 symmetric PO2 stretching frequency. Removal of most of the protein component from a 10:1 (lipid/protein, w/w) sample caused an ordering of the resultant lipid fractions. In contrast, removal of most of the protein component from a 20:1 sample resulted in no change in lipid order or thermotropic behavior. These observations are discussed in light of the roles played both by Ca2+ and protein in the spreading of surfactant. The power of FT-IR to acquire useful structural information from complex biological tissues is demonstrated.

Animals↗

Laterality and types of dyslexia.

The right shift theory of handedness and cerebral specialization suggests that there is an underlying substrate of random lateral asymmetries in all higher animals and a specific factor in humans which increases the probability of left hemisphere advantage. The specific factor displaces the random distribution along a continuum of asymmetry in favour of the left hemisphere and the right hand. The distribution of handedness in families can be explained if the shift to dextrality depends on a single gene, rs +, when the frequency of the gene is estimated from the proportion of dysphasics with unilateral lesions of the left versus the right hemisphere. The gentoype proportions suggested a genetic balanced polymorphism with heterozygote advantage for laterality and ability. Application of the model to developmental dyslexia led to the hypothesis that both homozygotes (rs -- and rs ++ genotypes) are at risk for reading. The critical question was whether the type of cognitive problem differs as expected, speech based processing for the rs -- and non-speech based for the rs ++. The former should include more left and mixed handers, while the latter should be more strongly dextral than controls. Evidence for this double dissociation between type of cognitive disability and type of handedness has been found in poor readers and in other samples.

Cognition↗