Healthcare cost variation in patients with heart failure: a nationwide study.

OBJECTIVE: Heart failure (HF) imposes a major economic burden; however, the individual management for patients varies, potentially leading to large cost heterogeneity. The aim of this study was to investigate the spectrum of health cost by patients with HF and factors associated with high direct health cost. STUDY DESIGN: This was a nationwide, retrospective longitudinal study. METHODS: Using Danish nationwide registries from 2012 to 2015, we identified all patients aged >18 years with a first-time diagnosis of HF. Total health costs were investigated using two perspectives-at index and during 3 years of follow-up. Patients were investigated by decile cost groups. A multivariable logistic regression was used to identify variables associated with being in the highest cost decile compared with the rest (90%). RESULTS: A total of 11,170 patients with HF were included, and those in the highest cost decile (n = 1117, 10%) were younger (69 vs. 75 years), fewer were females (34% vs. 43%), and more were inpatients (83% vs. 70%) compared with the rest of the patients with HF (n = 10,053, 90%). Patients in the highest cost decile (10%) incurred a 30 times higher cost with a mean total health cost in index year of €86,607 compared with €2893 for patients in lowest cost decile (10%). The results were similar for 3 years aggregated (€139,473 vs. €4086), corresponding to a 34 times higher cost. CONCLUSION: In patients with HF, a large total health cost heterogeneity exists with younger age, inpatient admittance, male sex, and comorbidities being associated with a higher likelihood of belonging to the highest cost group.

Spot size measurement of a deuterium-tritium dense plasma focus using neutron radiography.

Neutron radiography is a technique uniquely suited to applications in nuclear diagnostics, non-destructive testing, and subcritical experiments. The spatial resolution of neutron radiographs is degraded by optical blur in the imaging system and the neutron source size, where the ideal source is point-like to optimize the point-spread function. A potential neutron source for radiography is the dense plasma focus (DPF), a coaxial Z-pinch that produces thermonuclear and beam-target neutrons. To assess if the source size is suitable for radiography, a neutron imaging system was used to measure the source size of the 4 MA Sodium DPF at the Nevada National Security Site operating with deuterium-tritium gas-fill. The source size was measured using the edge-spread function of tungsten objects, each having a rolled (convex) edge. The spot size was found to be 7-12 mm full-width at half-max (FWHM) assuming a Gaussian source, though comparison is presented for Lorentzian and Bennett distributions. The average FWHM was found to be 8.6 ± 1.2 mm vertically and 10.8 ± 1.2 mm horizontally with respect to the image plane, averaging over varied edges and alignments. The results were sensitive to source alignment and edge metrology, which introduced notable uncertainties. These results are consistent with separate experimental measurements as well as magnetohydrodynamics simulations of this DPF, which suggest that neutron production can originate from pinches ∼5-7 mm off-axis. These results suggest that the DPF should be used for radiography at low magnification (M < 1) where spot size does not dominate spatial blur.

Identification and expression of gastrin and cholecystokinin mRNAs from the turtle, Pseudemys scripta: evidence of tissue-specific tyrosyl sulfation(1).

Gastrin and cholecystokinin (CCK) are related peptide hormones expressed in the brain and gut of vertebrates. In this study, complementary DNAs have been characterised from the red-eared slider turtle, Pseudemys scripta. The encoded preproCCK contains mono and dibasic endoproteolytic processing sites for formation of the previously identified CCK-70, CCK-40 and CCK-8 products, whereas preprogastrin contains two dibasic processing sites for the generation of gastrin-52. Alignment of the predicted preprohormone structures with those of other species, showed that preproCCK has been well conserved among all vertebrates, whereas progastrin is less conserved. Both gastrin and CCK mRNA display expression patterns similar to their mammalian counterparts, with CCK being expressed in the brain, duodenum and small intestine, and gastrin in the antrum. Heterologous expression of turtle preprogastrin in a mammalian endocrine cell line led to production of carboxyamidated gastrin-52 as observed in turtle antrum. However, in contrast to the non-sulfated endogenous peptide, the heterologously expressed gastrin was completely Tyr sulfated. Consequently, it appears that either gastrin producing cells in the turtle gut do not express tyrosylprotein sulfotransferases or the enzyme(s) present in turtle antrum is unable to sulfate turtle gastrin.

The population genetics of sperm displacement.

This article reports the results of some sperm displacement experiments, as well as the results of a theoretical study of selection arising from genetic differences in displacing ability. The experimental work involved the use of three genetic marker stocks in double and triple matings. The speed of displacement following the matings was determined by scoring the progeny of each female daily. There were clear differences between strains in their displacing ability. It is shown how new information concerning the displacement process results when three markers are used; however, no new light is shed by these experiments on the mechanism of displacement. The theoretical study of selection resulting from displacement uses a one-locus, two-allele model in which three diploid male genotypes confer different displacing abilities. The results indicate stable equilibria if (1) there is heterosis, and (2) there are certain nontransitive relationships in displacing ability among the different kinds of double matings. Some evolutionary consequences are discussed in which sperm displacement is regarded as a form of sexual selection.

Selection components in background replacement lines of Drosophila.

Selection components analysis was performed in lines of Drosophila melanogaster at three times during substitution backcrossing. The initial two lines were inbred isofemale lines from natural populations in California, and one had the spread wing mutation eagle. The selection components analysis revealed aspects of the genetic structure of the determinants of fitness by demonstrating changes in the marginal fitnesses of the eagle locus. Differences among backgrounds essentially disappeared by the 20th generation of backcrossing, suggesting that the previously observed differences were attributable to linkage disequilibrium. The method of bootstrapping was used as a novel means of determining statistical confidence in selection components.

Molecular structure and genetic mapping of the mouse gastrin gene.

The mouse gastrin gene has three exons totalling 460 bp and a deduced preprogastrin of 101 amino acids. The sequence of murine gastrin-34 is 94% identical to rat gastrin-34 and 76% identical to human gastrin-34. At Arg79, mouse progastrin has a unique cleavage site that might allow species-specific synthesis of gastrin-13. Northern analysis and RT-PCR demonstrated that gastrin gene transcripts are abundant in mouse stomach and duodenum and present at low levels in brain, ovary and pancreas, similar to the pattern described for other mammals. The gastrin gene was mapped to the distal region of mouse chromosome 11.

A distal Sp1-element is necessary for maximal activity of the human gastrin gene promoter.

Studies of transgenic mice have shown that transcriptional control of the gastrin gene exhibits significant species differences. Transfection of the human gastrin promoter in murine cells have depicted proximal Sp1, E-box and CACC elements as the major determinants of transcription. We have examined cis-regulatory elements of the human promoter on a human gastrin expressing cell line and find that a distal -135 to -142 Sp1 element is necessary for maximal activity. Alignment of the mouse and human promoters shows that the proximal human Sp1 and CACC elements are not conserved, whereas the E-box element is retained. The distal Sp1 element is present in mouse but exhibits a C to T transition in the core that is likely to reduce binding affinity of Sp1. We conclude that gastrin gene transcription is regulated by distinct elements in man and rodents.

An ELISA for grancalcin, a novel cytosolic calcium-binding protein present in leukocytes.

Grancalcin is a newly discovered cytosolic calcium-binding protein, belonging to the group of EF-hand proteins. Grancalcin is specifically associated with cells originating in the bone marrow. Grancalcin binds reversibly to secretory vesicles and plasma membranes in human neutrophils and might therefore play a role in the regulation of vesicle/granule exocytosis. We describe here the production of recombinant grancalcin, the generation of antibodies to the protein and the development of a specific, accurate and sensitive ELISA for the detection of human leukocytic grancalcin. This ELISA may be useful for monitoring leukocyte infiltration into tissues.

Genetic and environmental stress, and the persistence of populations.

Many populations of endangered species have to cope both with stressful and deteriorating environmental conditions (mostly the primary cause of the endangerment) and with an increase in homozygosity due to genetic drift and/or inbreeding in small isolated populations. The latter will result in genetic stress often accompanied by a decrease in fitness (inbreeding depression). We have studied the consequences of genetic stress, under optimal as well as stressful environmental conditions, for the fitness and persistence of small populations using Drosophila melanogaster as a model system. The results show that, already under optimal environmental conditions, an increase in homozygosity or inbreeding both impairs fitness and increases the extinction risk of populations significantly. Under environmental stress, however, these effects become greatly enhanced. More important, the results show that the impact of environmental stress becomes significantly greater for higher inbreeding levels. This explicitly demonstrates that genetic and environmental stress are not independent but can act synergistically. This apparent interaction may have important consequences for the conservation of endangered species.

Composite action of three GC/GT boxes in the proximal promoter region is important for gastrin gene transcription.

The proximal region of the human gastrin gene promoter contains three GC/GT boxes at positions -140 to -134 bp, -108 to -102 bp and -67 to -61 bp. In this study we have examined the significance of the three elements, and their role in Sp1 and Sp3 mediated gastrin transcription. In AGS cells, mutation of each of the boxes caused a moderate decrease in promoter activity from 33 to 63%, whereas double or triple mutations reduced activity to 3-12%. In Drosophila cells Sp1 activated the promoter, mainly through the distal GC box. Similarly, co-transfection of heterologous promoter constructs revealed that only the distal GC box increased activation by Sp1. The effect of Sp3 was cell-line dependent, since Sp3 inhibited the gastrin promoter activity in AGS cells and caused a synergistic activation of the Sp1 stimulated gastrin promoter in Drosophila cells. Both effects were dependent on the C-terminal DNA binding domain of Sp3. The results indicates that the combined effect of the GC/GT boxes and the ratio between Sp1 and Sp3 are important for gastrin gene expression.

An efficient cellular system for mutational analysis of prohormone processing.

A novel system for heterologous expression of prohormones based on transient transfection of the HIT beta-cell line was established using human progastrin as a model. Progastrin was expressed at high levels compared to other gene transfer systems in endocrine cells, and the processing pattern was similar to that of normal antral gastrin cells. Thus, gastrin was partially tyrosine O-sulfated and carboxyamidated. Cell extracts contained mainly gastrin-17 and gastrin-34 and the corresponding glycine-extended forms. In contrast, the media contained more incompletely processed gastrin forms. This suggests that gastrin was directed to the regulated secretory pathway but that some progastrin products were constitutively secreted. Glucose increased both the level of gastrin gene expression and maturation to carboxyamidated peptides, indicating that glucose influences the activity of the amidation enzyme complex, peptidylglycine alpha-amidating mono-oxygenase (PAM), in insulin cells. Mutational analysis of tyrosine sulfation of gastrin demonstrated that substitution of the uncharged residue carboxy-terminal to the tyrosine with an acidic residue does not increase sulfation in contrast to previous results, where the amino-terminal residue was replaced with an acidic residue. The mutant peptides displayed sulfation-dependent processing, supporting our recent suggestion that tyrosine sulfation increases the proteolytic processing of prohormones.

Vitamin D3 effects on basal and cAMP modulated expression of cholecystokinin and somatostatin genes in a rat medullary thyroid carcinoma cell line [CA-77].

The regulation of cholecystokinin and somatostatin expression by vitamin D and cyclic AMP in the rat medullary thyroid carcinoma cell line CA-77 was investigated. Treatment with 100 nmol/l vitamin D did not affect cholecystokinin mRNA and peptide concentrations significantly; somatostatin mRNA level increased 6 times and the somatostatin peptide concentration increased 2-fold after 5 days of drug treatment. Under the same experimental conditions cyclic AMP increased cholecystokinin mRNA level 4.5 times and the cellular cholecystokinin-peptide concentration 2-fold; somatostatin mRNA and peptide concentrations were not significantly changed. Cyclic AMP stimulated peptide secretion from the cells were not affected by vitamin D, but cyclic AMP mediated increase in CCK peptide concentration was significantly inhibited by vitamin D (p < 0.05).

Neuropsychological outcome of head injury using a short battery.

The purpose of this study was to demonstrate that a semi-flexible neuropsychological test battery would accurately identify and discriminate head trauma severity levels. In addition, it was intended to demonstrate that this same battery could discriminate head trauma individuals from individuals with other diagnoses. Participants were patients referred for a neuropsychological evaluation. All patients were administered a battery of tests taking approximately 3 hours. It was found that the semi-flexible battery was able to differentiate patients grouped into six different severity levels of loss of consciousness (LOC). In addition, the battery was able to differentiate patients with diagnoses including mental health diagnosis, CVA, dementia, and head trauma. These results support previous findings, but utilized a semi-flexible test battery to do so. This shorter battery is beneficial to patient, neuropsychologists, and managed care providers alike.

Ethical evaluation of hypnosis research: a survey of investigators and their institutional review boards.

We surveyed hypnosis researchers and Institutional Review Boards (IRBs) with regard to the ethical evaluation of research protocols. Researchers and IRB administrators were independently surveyed within the same institutions. Both objective and free response items were used to address substantive issues such as deception and at-risk populations, as well as practical matters such as paperwork. Parallel questions allowed a point-counterpoint between researchers and IRBs. Overall, the results suggest that IRBs do not treat hypnosis research differently than other types of research. We end with recommendations for facilitating interactions between hypnosis researchers and their IRBs.

The influence of male and female body size on copulation duration and fecundity in Drosophila melanogaster.

We studied two components of the mating system, copulation duration and early fecundity, in relation to body size in Drosophila melanogaster. Body size variation was created experimentally by varying the degree of crowding (starvation) among larvae from an inbred strain, keeping the genetics and temperature as constant as possible. Hence, in contrast to most previous studies, where genetic and environmental variation have been confounded, we aimed at investigating how much pure phenotypic variation could influence copulation duration and early fecundity. It is shown that copulation duration and fecundity both strongly dependent on female body size, but either not or much less so on male body size. Small females mate faster than medium or large females and small females have the lowest fecundity. Among males, medium-size males are more fecund than smaller or larger males, resulting in stabilising selection for intermediate male size. These results are in contrast with previous findings.