Cost-effectiveness and Benefit-to-Harm Ratio of Risk-Stratified Screening for Breast Cancer: A Life-Table Model.

IMPORTANCE: The age-based or "one-size-fits-all" breast screening approach does not take into account the individual variation in risk. Mammography screening reduces death from breast cancer at the cost of overdiagnosis. Identifying risk-stratified screening strategies with a more favorable ratio of overdiagnoses to breast cancer deaths prevented would improve the quality of life of women and save resources. OBJECTIVE: To assess the benefit-to-harm ratio and the cost-effectiveness of risk-stratified breast screening programs compared with a standard age-based screening program and no screening. DESIGN, SETTING, AND POPULATION: A life-table model was created of a hypothetical cohort of 364 500 women in the United Kingdom, aged 50 years, with follow-up to age 85 years, using (1) findings of the Independent UK Panel on Breast Cancer Screening and (2) risk distribution based on polygenic risk profile. The analysis was undertaken from the National Health Service perspective. INTERVENTIONS: The modeled interventions were (1) no screening, (2) age-based screening (mammography screening every 3 years from age 50 to 69 years), and (3) risk-stratified screening (a proportion of women aged 50 years with a risk score greater than a threshold risk were offered screening every 3 years until age 69 years) considering each percentile of the risk distribution. All analyses took place between July 2016 and September 2017. MAIN OUTCOMES AND MEASURES: Overdiagnoses, breast cancer deaths averted, quality-adjusted life-years (QALYs) gained, costs in British pounds, and net monetary benefit (NMB). Probabilistic sensitivity analyses were used to assess uncertainty around parameter estimates. Future costs and benefits were discounted at 3.5% per year. RESULTS: The risk-stratified analysis of this life-table model included a hypothetical cohort of 364 500 women followed up from age 50 to 85 years. As the risk threshold was lowered, the incremental cost of the program increased linearly, compared with no screening, with no additional QALYs gained below 35th percentile risk threshold. Of the 3 screening scenarios, the risk-stratified scenario with risk threshold at the 70th percentile had the highest NMB, at a willingness to pay of £20 000 (US $26 800) per QALY gained, with a 72$26 888) vs £537 985 (US $720 900) less, would have 26.7% vs 71.4% fewer overdiagnoses, and would avert 2.9% vs 9.6% fewer breast cancer deaths, respectively. CONCLUSIONS AND RELEVANCE: Not offering breast cancer screening to women at lower risk could improve the cost-effectiveness of the screening program, reduce overdiagnosis, and maintain the benefits of screening

The role of asymmetric interactions on the effect of habitat destruction in mutualistic networks

Plant-pollinator mutualistic networks are asymmetric in their interactions: specialist plants are pollinated by generalist animals, while generalist plants are pollinated by a broad involving specialists and generalists. It has been suggested that this asymmetric ---or disassortative--- assemblage could play an important role in determining the equal susceptibility of specialist and generalist plants under habitat destruction. At the core of the argument lies the observation that specialist plants, otherwise candidates to extinction, could cope with the disruption thanks to their interaction with generalist pollinators. We present a theoretical framework that supports this thesis. We analyze a dynamical model of a system of mutualistic plants and pollinators, subject to the destruction of their habitat. We analyze and compare two families of interaction topologies, ranging from highly assortative to highly disassortative ones, as well as real pollination networks. We found that several features observed in natural systems are predicted by the mathematical model. First, there is a tendency to increase the asymmetry of the network as a result of the extinctions. Second, an entropy measure of the differential susceptibility to extinction of specialist and generalist species show that they tend to balance when the network is disassortative. Finally, the disappearance of links in the network, as a result of extinctions, shows that specialist plants preserve more connections than the corresponding plants in an assortative system, enabling them to resist the disruption.Comment: 14 pages, 7 figure

Differences in the signaling pathways of α1A- and α1B-adrenoceptors are related to different endosomal targeting

Aims: To compare the constitutive and agonist-dependent endosomal trafficking of α1A- and α1B-adrenoceptors (ARs) and to establish if the internalization pattern determines the signaling pathways of each subtype. Methods: Using CypHer5 technology and VSV-G epitope tagged α1A- and α1B-ARs stably and transiently expressed in HEK 293 cells, we analyzed by confocal microscopy the constitutive and agonist-induced internalization of each subtype, and the temporal relationship between agonist induced internalization and the increase in intracellular calcium (determined by FLUO-3 flouorescence), or the phosphorylation of ERK1/2 and p38 MAP kinases (determined by Western blot). Results and Conclusions: Constitutive as well as agonist-induced trafficking of α1A and α1B ARs maintain two different endosomal pools of receptors: one located close to the plasma membrane and the other deeper into the cytosol. Each subtype exhibited specific characteristics of internalization and distribution between these pools that determines their signaling pathways: α1A-ARs, when located in the plasma membrane, signal through calcium and ERK1/2 pathways but, when translocated to deeper endosomes, through a mechanism sensitive to β-arrestin and concanavalin A, continue signaling through ERK1/2 and also activate the p38 pathway. α1B-ARs signal through calcium and ERK1/2 only when located in the membrane and the signals disappear after endocytosis and by disruption of the membrane lipid rafts by methyl-β-cyclodextrin

Association between the c.*229C>T polymorphism of the topoisomerase IIb binding protein 1 (TopBP1) gene and breast cancer

Topoisomerase IIb binding protein 1 (TopBP1) is involved in cell survival, DNA replication, DNA damage repair and cell cycle checkpoint control. The biological function of TopBP1 and its close relation with BRCA1 prompted us to investigate whether alterations in the TopBP1 gene can influence the risk of breast cancer. The aim of this study was to examine the association between five polymorphisms (rs185903567, rs116645643, rs115160714, rs116195487, and rs112843513) located in the 30UTR region of the TopBP1 gene and breast cancer risk as well as allele-specific gene expression. Five hundred thirty-four breast cancer patients and 556 population controls were genotyped for these SNPs. Allele-specific Top- BP1 mRNA and protein expressions were determined by using real time PCR and western blotting methods, respectively. Only one SNP (rs115160714) showed an association with breast cancer. Compared to homozygous common allele carriers, heterozygous and homozygous for the T variant had significantly increased risk of breast cancer (adjusted odds ratio = 3.81, 95 % confidence interval: 1.63–8.34, p = 0.001). Mean TopBP1 mRNA and protein expression were higher in the individuals with the CT or TT genotype. There was a significant association between the rs115160714 and tumor grade and stage. Most carriers of minor allele had a high grade (G3) tumors classified as T2-T4N1M0. Our study raises a possibility that a genetic variation of TopBP1 may be implicated in the etiology of breast cancer

Description of the BRIGHTLIGHT cohort: the evaluation of teenage and young adult cancer services in England

Objective International recognition of the unique needs of young people with cancer is growing. Many countries have developed specialist age-appropriate cancer services believing them to be of value. In England, 13 specialist principal treatment centres (PTCs) deliver cancer care to young people. Despite this expansion of specialist care, systematic investigation of associated outcomes and costs has, to date, been lacking. The aim of this paper is to describe recruitment and baseline characteristics of the BRIGHTLIGHT cohort and the development of the bespoke measures of levels of care and disease severity, which will inform the evaluation of cancer services in England. Design Prospective, longitudinal, observational study. Setting Ninety-seven National Health Service hospitals in England. Participants A total of 1114 participants were recruited and diagnosed between July 2012 and December 2014: 55% (n=618) were men, mean age was 20.1 years (SD=3.3), most (86%) were white and most common diagnoses were lymphoma (31%), germ cell tumour (19%) and leukaemia (13%). Results At diagnosis, median quality of life score was significantly lower than a published control threshold (69.7 points); 40% had borderline to severe anxiety, and 21% had borderline to severe depression. There was minimal variation in other patient-reported outcomes according to age, diagnosis or severity of illness. Survival was lower in the cohort than for young people diagnosed during the same period who were not recruited (cumulative survival probability 4 years after diagnosis: 88% vs 92%). Conclusions Data collection was completed in March 2018. Longitudinal comparisons will determine outcomes and costs associated with access/exposure to PTCs. Findings will inform international intervention and policy initiatives to improve outcomes for young people with cancer

Application of the speed-duration relationship to normalize the intensity of high-intensity interval training

The tolerable duration of continuous high-intensity exercise is determined by the hyperbolic Speed-tolerable duration (S-tLIM) relationship. However, application of the S-tLIM relationship to normalize the intensity of High-Intensity Interval Training (HIIT) has yet to be considered, with this the aim of present study. Subjects completed a ramp-incremental test, and series of 4 constant-speed tests to determine the S-tLIM relationship. A sub-group of subjects (n = 8) then repeated 4 min bouts of exercise at the speeds predicted to induce intolerance at 4 min (WR4), 6 min (WR6) and 8 min (WR8), interspersed with bouts of 4 min recovery, to the point of exercise intolerance (fixed WR HIIT) on different days, with the aim of establishing the work rate that could be sustained for 960 s (i.e. 4×4 min). A sub-group of subjects (n = 6) also completed 4 bouts of exercise interspersed with 4 min recovery, with each bout continued to the point of exercise intolerance (maximal HIIT) to determine the appropriate protocol for maximizing the amount of high-intensity work that can be completed during 4×4 min HIIT. For fixed WR HIIT tLIM of HIIT sessions was 399±81 s for WR4, 892±181 s for WR6 and 1517±346 s for WR8, with total exercise durations all significantly different from each other (P<0.050). For maximal HIIT, there was no difference in tLIM of each of the 4 bouts (Bout 1: 229±27 s; Bout 2: 262±37 s; Bout 3: 235±49 s; Bout 4: 235±53 s; P>0.050). However, there was significantly less high-intensity work completed during bouts 2 (153.5±40. 9 m), 3 (136.9±38.9 m), and 4 (136.7±39.3 m), compared with bout 1 (264.9±58.7 m; P>0.050). These data establish that WR6 provides the appropriate work rate to normalize the intensity of HIIT between subjects. Maximal HIIT provides a protocol which allows the relative contribution of the work rate profile to physiological adaptations to be considered during alternative intensity-matched HIIT protocols

A cross-sectional survey of healthcare professionals to determine what they believe constitutes 'specialist' care for teenage and young adult patients with cancer

Objectives: To examine the attitudes of UK healthcare professionals towards what they believe constitutes specialist care for teenage and young adult (TYA) patients with cancer, to determine which factors they considered to be the most important components of specialist TYA care, and whether opinion varied between clinical specialties and reflected the drivers for care improvements within National Health Service (NHS) policy. Design and methods: The study utilised a crosssectional survey, using Likert scales, to assess attitudes towards specialist care. Responses were grouped using model-based clustering methods implemented in LatentGold 4.5. Setting: Participants from 98 NHS trusts in the UK were invited to participate in the study. Participants: 691 healthcare professionals involved in the management of TYA patients were approached; of these, 338 responded. Results: 338 healthcare professionals responded (51.9% of those invited). Responses were grouped into three clusters according to the pattern of responses to the questions. One cluster rated age-appropriate care above all else, the second rated both age and site-appropriate care highly while the third assigned more importance to site-specific care. Overall, the psychosocial and supportive aspects of care were rated highest while statements relating to factors known to be important (access to clinical trials, treatment at a high volume centre and specialist diagnostics) were not rated as highly as expected. Conclusions: Attitudes varied widely between professionals treating TYA patients with cancer as to what constitutes key aspects of specialist care. Further work is needed to quantify the extent to which this influences practice

Extremal measures maximizing functionals based on simplicial volumes

We consider functionals measuring the dispersion of a d-dimensional distribution which are based on the volumes of simplices of dimension k ≤ d formed by k + 1 independent copies and raised to some power δ. We study properties of extremal measures that maximize these functionals. In particular, for positive δ we characterize their support and for negative δ we establish connection with potential theory and motivate the application to space-filling design for computer experiments. Several illustrative examples are presented