Making Informed Choices On Incorporating Chemoprevention into carE (MiCHOICE, SWOG 1904): Design and methods of a cluster randomized controlled trial.

INTRODUCTION: Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy. METHODS/DESIGN: We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation. RESULTS/DISCUSSION: With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S. TRIAL REGISTRATION: NCT04496739.

The odd log-logistic generalized exponential distribution: Application on survival times of chemotherapy patients data.

Background: The creation of developing new generalized classes of distributions has attracted applied and theoretical statisticians owing to their properties of flexibility. The development of generalized distribution aims to find distribution flexibility and suitability for available data. In this decade, most authors have developed classes of distributions that are new, to become valuable for applied researchers. Methods: This study aims to develop the odd log-logistic generalized exponential distribution (OLLGED), one of the lifetime newly generated distributions in the field of statistics. The advantage of the newly generated distribution is the heavily tailed distributed lifetime data set. Most of the probabilistic properties are derived including generating functions, moments, and quantile and order statistics. Results: Estimation of the model parameter is done by the maximum likelihood method. The performance of parametric estimation is studied through simulation. Application of OLLGED and its flexibilities is done using two data sets and while its performance is done on the randomly simulated data set. Conclusions: The application and flexibility of the OLLGED are ensured through empirical observation using two sets of lifetime data, establishing that the proposed OLLGED can provide a better fit in comparison to existing rival models, such as odd generalized log-logistic, type-II generalized log-logistic, exponential distributions, odd exponential log-logistic, generalized exponential, and log-logistic.

Blackbody radiation shift assessment for a lutetium ion clock.

The accuracy of state-of-the-art atomic clocks is derived from the insensitivity of narrow optical atomic resonances to environmental perturbations. Two such resonances in singly ionized lutetium have been identified with potentially lower sensitivities compared to other clock candidates. Here we report measurement of the most significant unknown atomic property of both transitions, the static differential scalar polarizability. From this, the fractional blackbody radiation shift for one of the transitions is found to be -1.36(9) × 10-18 at 300 K, the lowest of any established optical atomic clock. In consideration of leading systematic effects common to all ion clocks, both transitions compare favorably to the most accurate ion-based clocks reported to date. This work firmly establishes Lu+ as a promising candidate for a future generation of more accurate optical atomic clocks.

Development and validation of a clinical prediction rule to identify suspected breast cancer: a prospective cohort study.

BACKGROUND: The number of primary care referrals of women with breast symptoms to symptomatic breast units (SBUs) has increased exponentially in the past decade in Ireland. The aim of this study is to develop and validate a clinical prediction rule (CPR) to identify women with breast cancer so that a more evidence based approach to referral from primary care to these SBUs can be developed. METHODS: We analysed routine data from a prospective cohort of consecutive women reviewed at a SBU with breast symptoms. The dataset was split into a derivation and validation cohort. Regression analysis was used to derive a CPR from the patient's history and clinical findings. Validation of the CPR consisted of estimating the number of breast cancers predicted to occur compared with the actual number of observed breast cancers across deciles of risk. RESULTS: A total of 6,590 patients were included in the derivation study and 4.9% were diagnosed with breast cancer. Independent clinical predictors for breast cancer were: increasing age by year (adjusted odds ratio 1.08, 95% CI 1.07-1.09); presence of a lump (5.63, 95% CI 4.2-7.56); nipple change (2.77, 95% CI 1.68-4.58) and nipple discharge (2.09, 95% CI 1.1-3.97). Validation of the rule (n = 911) demonstrated that the probability of breast cancer was higher with an increasing number of these independent variables. The Hosmer-Lemeshow goodness of fit showed no overall significant difference between the expected and the observed numbers of breast cancer (χ(2)HL: 6.74, p-value: 0.56). CONCLUSIONS: This study derived and validated a CPR for breast cancer in women attending an Irish national SBU. We found that increasing age, presence of a lump, nipple discharge and nipple change are all associated with increased risk of breast cancer. Further validation of the rule is necessary as well as an assessment of its impact on referral practice.

Radiometrical, hormonal and biological correlates of skeletal growth in the female rat from birth to senescence.

OBJECTIVE: We investigated the skeletal growth profile of female rats from birth to senescence (100weeks) on the basis of sequential radiometrical, hormonal and biochemical parameters. DESIGN: Weaning rats entered the study which was divided into two sections: a) sequential measurements of vertebral and tibial growths and bone mineral density (BMD), estimation of mineral content of the entire skeleton (BMC) and chemical analysis of vertebral Ca; and b) determination of basal and pulsatile growth hormone (rGH), insulin-like growth hormone (IGF-I), estradiol (E2), parathyroid hormone (PTH), osteocalcin (OC) and urinary d-pyridinoline (dp) throughout the experimental period. RESULTS: Vertebral and tibial growths ceased at week 25 whereas BMD and BMC as well as total vertebral Ca exhibited a peak bone mass at week 40. rGH pulsatile profiles were significantly higher in younger animals coinciding with the period of active growth and IGF-I peaked at 7weeks, slowly declining thereafter and stabilizing after week 60. OC and dp closely paralleled IGF-I coinciding with the period of enhanced skeletal growth, remaining thereafter in the low range indicative of reduced bone turnover. E2 increased during reproductive life but the lower values subsequently recorded were still in the physiological range, strongly suggesting a protective role of this steroid on bone remodeling. PTH followed a similar profile to E2, but the significance of this after completion of growth remains unclear. CONCLUSIONS: Mechanisms governing skeletal growth in the female rat appear similar to those in humans. Bone progression and attainment of peak bone mass are under simultaneous control of rGH, IGF-I and calciotropic hormones and are modulated by E2. This steroid seems to protect the skeleton from resorption before senescence whereas the role of PTH in this context remains uncertain.

Impacts of dietary antioxidants and flight training on post-exercise oxidative damage in adult parrots.

After intense physical activity animals generally experience a rise in metabolic rate, which is associated with a proliferation of pro-oxidants. If unchecked, these pro-oxidants can cause damage to DNA and peroxidation of lipids in cell walls. Two factors are thought to ameliorate post-exercise oxidative damage, at least in mammals: dietary antioxidants and exercise training. So far it is unknown whether birds benefit similarly from exercise training, although a positive effect of dietary antioxidants on take-off flight has been indicated. In this experiment, we maintained captive wildtype budgerigars Melopsittacus undulatus on enhanced (EQ) or reduced quality (RQ) diets differing in levels of the dietary antioxidants retinol, vitamin C and alpha-tocopherol for 12 months. Birds were then regularly trained to perform take-off escape flights, a strenuous and biologically relevant form of exercise. For these adult budgerigars, regular exercise training improved escape flight performance, particularly in males on the EQ diet. In terms of oxidative damage, post-exercise levels of malondialdehyde (MDA), a by-product of lipid peroxidation, were significantly decreased after 9 weeks of flight training than after a single exercise session. Thus, individuals achieved faster escape flights with lower oxidative damage, after training. Also, birds that were fatter for their skeletal size initially had higher post-exercise MDA levels than thinner birds, but this relationship was broken by 9 weeks of flight training. Interestingly, there was no impact of diet quality on levels of MDA, suggesting that improved protection against oxidative damage for all birds was due to an up-regulation of endogenous antioxidant systems. Given their diversity, bird species provide rich research opportunities for investigating the interactions between exercise training, pro-oxidants production and antioxidant defences.

The effects of short-term antioxidant supplementation on oxidative stress and flight performance in adult budgerigars Melopsittacus undulatus.

Antioxidants are known to play an important role in quenching reactive oxygen species (ROS), thus ameliorating oxidative stress. Since increased metabolism associated with exercise can increase oxidative stress, dietary antioxidants may be a limiting factor in determining aspects of physical performance. Here we tested whether oxidative stress associated with flight exercise of captive adult budgerigars, Melopsittacus undulatus differed after they received a diet containing either enhanced (EQ) or reduced levels (RQ) of a nutritional supplement (Nutrivit) rich in antioxidants for 4 weeks. We also assessed differences in take-off escape time, a potential fitness-determining physiological capability. Oxidative stress was measured in two ways: comet assay to measure DNA damage; and analysis of malondialdehyde (MDA), a by-product of lipid peroxidation. Flight exercise appeared to increase oxidative stress. Moreover, birds had a higher percentage of intact DNA (fewer alkali labile sites) in one comet measure and lower levels of MDA after an EQ diet than after an RQ diet. We found no difference in flight performance between the two diets. Our results suggested that birds exerted maximum effort in escape flights, regardless of diet. However, this was at a cost of increased oxidative stress post-flight when on a reduced quality diet, but not when on an enhanced, antioxidant-rich diet. We suggest that dietary antioxidants may prove important in reducing exercise-related costs through multiple physiological pathways. Further work is necessary to fully understand the effects of antioxidants and oxidative stress on exercise performance in the longer term.

COX inhibitors modulate bFGF-induced cell survival in MCF-7 breast cancer cells.

Basic fibroblast growth factor (bFGF) serves as a modulator of survival in breast cancer cells. The mechanisms by which bFGF transduces the anti-apoptotic signal and interacts with COX inhibitors were investigated. bFGF reduced apoptosis in MCF-7 breast cancer cells and up-regulated the expression of mitocondrial Bcl-2, whereas COX inhibitors meloxicam (selective COX-2) and aspirin (non-selective), induced apoptosis. bFGF up-regulated survivin protein expression and induced cdc-2 phosphorylation moderately at early (2-6 h), and substantially at late (24 h), time-points. Survivin mRNA expression was up-regulated only at the later time-point. COX inhibitors prevented up-regulation of survivin protein expression at both 2 and 24 h and prevented early modest increases in cdc-2 phosphorylation. Up-regulation of survivin mRNA was not found to be modulated by the COX-2 inhibitor meloxicam. bFGF regulation of survivin expression was found to be ERK1/2 kinase dependent and bFGF-induced phosphorylation of c-raf was prevented by the COX-2 inhibitor. bFGF was, however, unable to induce COX-2 protein expression or modulate COX-2 activity in MCF-7 cells as evidenced by unaltered PGE(2) production. These results indicate that bFGF regulates survivin expression in MCF-7 breast cancer cells by signaling through an ERK1/2 dependent pathway. COX-2 inhibitors can modulate bFGF-induced survivin expression in a COX-2 independent manner.

Contribution of reactive oxygen species to cartilage degradation in rheumatic diseases: molecular pathways, diagnosis and potential therapeutic strategies.

Inflammatory joint diseases are of considerable socio-economic significance. However, mechanisms of cartilage destruction are so far only poorly understood. This review is dedicated to reactive oxygen species (ROS) like superoxide anion radicals, hydrogen peroxide, singlet oxygen, hypochlorous acid, hydroxyl radicals and nitric oxide that are generated under inflammatory conditions and also to their potential contribution to cartilage degradation. First, the relevance of rheumatic diseases and potential mechanisms of cartilage degradation are discussed in this review, followed by the description of the chemical constituents and the molecular architecture of articular cartilage as well as the different cell types that play a role in inflammation and cartilage destruction. Methods of the assessment of cartilage degeneration are also shortly discussed. In the main chapter of this review the characteristics of individual ROS, their generation under in vivo conditions as well as their reactivities with individual cartilage components are discussed. Because of the low selectivity of ROS, useful "markers" of cartilage degradation allowing the differentiation of effects induced by individual ROS are also discussed. In the last chapter current therapeutic concepts of the treatment of rheumatic diseases are reviewed. The recently developed "anti-TNF-alpha" therapy that is primarily directed against neutrophilic granulocytes that are powerful sources of ROS and, therefore, important mediators of joint degeneration are emphasised.

Lipid analysis of bronchoalveolar lavage fluid (BAL) by MALDI-TOF mass spectrometry and 31P NMR spectroscopy.

Despite the high clinical relevance, only the cellular moiety of bronchoalveolar lavage (BAL) has been intensively investigated and is used for diagnosis purposes. On the other hand, the cell-free fluid is, by far, less characterized. Although this fluid represents a relatively simple mixture of only a few different phospholipids (mainly phosphatidylcholine, phosphatidylglycerol and cholesterol), methods for the routine analysis of these fluids are still lacking. In the present investigation we have applied, for the first time, MALDI-TOF mass spectrometry, as well as 31P NMR spectroscopy to the analysis of organic extracts of bronchoalveolar lavage fluids. BAL from different mammals (rat, minipig, rabbit and man) were investigated and, for means of comparison, organic extracts of lung tissue were also examined. Both applied methods provide fast and reliable information on the lipid composition of the bronchoalveolar lavage. However, despite of its comparably low sensitivity, 31P NMR spectroscopy detects all phospholipid species in a single experiment and with the same sensitivity, whereas MALDI-TOF fails in the detection of phosphatidylethanolamine in the presence of higher quantities of phosphatidylcholine. In contrast, MALDI-TOF mass spectrometry is more suitable for the detection of cholesterol and the determination of the fatty acid composition of the individual phospholipids, especially lysolipids. It will be shown that all BALs exhibit significant, species-dependent differences that mainly concern the content of phosphatidylglycerol and lyso-phosphatidylcholine. It is concluded that both methods are suitable tools in lipid research due to the (in comparison to alternative methods) simplicity of performance.

Possible medication errors in home healthcare patients.

OBJECTIVE: To determine the frequency of possible medication errors in a population of older home healthcare patients according to expert panel objective criteria. DESIGN: A cross-sectional survey. SETTING: Two of the largest urban home healthcare agencies in the United States. PARTICIPANTS: Home healthcare patients age 65 and older admitted to selected offices of these agencies between October 1996 and September 1998. MEASUREMENTS: We used two sets of consensus-based expert panel criteria to define possible medication errors. The Home Health Criteria identify patients with patterns of medication use and signs and symptoms that indicate sufficient likelihood of a medication-related problem to warrant reevaluating the patient. The Beers criteria identify medications that experts have deemed generally inappropriate for older patients. RESULTS: The 6,718 study subjects took a median of five drugs; 19% were taking nine or more medications. A possible medication error was identified for 19% of patients according to Home Health Criteria, 17% according to the Beers criteria, and 30% according to either. Possible errors increased linearly with number of medications taken. When patients taking one to three medications were compared with those taking nine or more drugs, the percentages with possible errors were, respectively, 10% and 32% for the Home Health Criteria, 8% and 32% for the Beers criteria, and 16% and 50% for both. CONCLUSION: Nearly one-third of the home healthcare patients surveyed had evidence of a potential medication problem or were taking a drug considered inappropriate for older people. More-effective methods are needed to improve medication use in this vulnerable population.

Haplotype variation and linkage disequilibrium in 313 human genes.

Variation within genes has important implications for all biological traits. We identified 3899 single nucleotide polymorphisms (SNPs) that were present within 313 genes from 82 unrelated individuals of diverse ancestry, and we organized the SNPs into 4304 different haplotypes. Each gene had several variable SNPs and haplotypes that were present in all populations, as well as a number that were population-specific. Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency. Haplotypes generally had more information content (heterozygosity) than did individual SNPs. Our analysis of the pattern of variation strongly supports the recent expansion of the human population.

Limits for the detection of (poly-)phosphoinositides by matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS).

Matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been recently established as a powerful tool for the analysis of biomolecules. Here, MALDI-TOF MS was used for the detection of (poly-)phosphoinositides (PPI). PPI possess higher molecular weights than other phospholipids and a high phosphorylation-dependent negative charge. Both features affect the MALDI detection limits expressed as the minimum of analyte on the sample plate resulting in a signal-to-noise-ratio of S/N = 5. Using 2,5-dihydroxybenzoic acid (DHB) as matrix the detection limit for phosphatidylinositol (PI) is seven times higher than for phosphatidylcholine (PC) and further increases with increasing phosphorylation or in mixtures with other well-detectable phospholipids. For phosphatidylinositol-tris-phosphate (PIP3) in a mixture with PC, the limit is about 20 times higher than for PI. The consequences for the experimental conditions are discussed. It is advisable to pre-separate PPI from biological lipid mixtures prior to the application of MALDI-TOF MS.

The effect of Zn(2+) on the secondary structure of a histidine-rich fusogenic peptide and its interaction with lipid membranes.

Membrane fusion between uncharged lipid vesicles can be triggered by the peptide sequence 'B18' from the fertilization protein 'bindin', but it only proceeds efficiently in the presence of Zn(2+) ions. We studied (i) the interaction of Zn(2+) with the fusogenic peptide B18, (ii) the binding of B18 to 1-palmitoyl-2-oleoylglycero-3-phosphocholine (POPC), and (iii) the ternary system POPC/B18/Zn(2+). The complex formation of Zn(2+) with the central histidine-rich motif of B18 appears to shift the secondary structure away from a beta-sheet towards an alpha-helical conformation. Here we observe for the first time an essentially alpha-helical structure of the peptide when immersed in POPC bilayers which appears to represent its functional fusogenic state. Infrared linear dichroism suggests a peripheral, oblique insertion mode of B18, mediated by the hydrophobic patches along one side of the amphipathic peptide. Furthermore, the hydration level of the peptide is reduced, suggesting that the hydrophobic region of the bilayer is involved in the lipid/peptide interactions. The hydration capacity of the POPC/B18/Zn(2+) system is distinctly smaller than that of POPC/Zn(2+) without peptide. The accompanying decrease in the number of tightly bound water molecules per lipid can be interpreted as a reduction in the repulsive 'hydration' forces, which usually prevent the spontaneous fusion of lipid vesicles. Binding of the B18 peptide in the presence of Zn(2+) effectively renders the membrane surface more hydrophobic, thus allowing fusion to proceed.