Adaptive dosing of anticancer drugs in neonates: facilitating evidence-based dosing regimens

PURPOSE: Selection of the most appropriate chemotherapy dosing regimens for neonates treated within the first weeks of life represents a significant clinical dilemma. Due to a lack of information relating to the clinical pharmacology of anticancer drugs in these challenging patients, current dosing guidelines are based on limited scientific rationale. In the current study, we investigate the utilisation of therapeutic drug monitoring approaches in neonates with localised hepatoblastoma, Wilms' tumour and stage 4S neuroblastoma, being treated with widely used anticancer drugs. METHODS: Plasma concentrations of cisplatin, vincristine, etoposide and carboplatin were quantified in two neonates being treated within the first 3 weeks of life and in a 32-week preterm infant treated at a gestational age of 40 weeks. Therapeutic drug monitoring was carried out where appropriate, based on the pharmacokinetic data obtained in conjunction with clinical response and toxicity. RESULTS: Treatment of a child aged 2 weeks with a recommended cisplatin dose reduction for weight to 1.8 mg/kg resulted in achievement of unbound cisplatin plasma concentrations of 0.01-0.08 µg/mL, markedly lower than exposures previously reported in infants and older children. A dose increase to 2.7 mg/kg was implemented, leading to the achievement of levels more in-line with those previously reported. This increased dose level was well tolerated over six courses of treatment, resulting in a good response to cisplatin monotherapy and the patient remains in remission at 3.5 years. In contrast, a 50 % vincristine dose reduction for weight in a 3-week-old neonate resulted in plasma concentrations comparable to levels observed in older children, leading to successful treatment and continued remission at 2 years. In a third patient, etoposide and carboplatin clearance values normalised to body weight were comparable to those reported in older children, resulting in comparatively lower exposures following reduced dosing. CONCLUSIONS: The current report provides unique data on the pharmacokinetics of several widely used anticancer drugs in neonates treated within the first few weeks of life. The provision of these data acts as a useful reference point to support future dosing decisions to be made by clinicians in the treatment of these challenging patients

Childhood adversity, attachment security, and adult relationships: A preliminary study

Several evolutionary theorists have linked early rearing context to later reproductive strategy, hypothesizing that strategies differentiate during development as functional responses to ecological characteristics, by individuals or through parental manipulation. Attachment security has been proposed as a mediator. In this study, 40 young adults were given a multidimensional assessment, including the Hazen and Shaver Adult Attachment Questionnaire. Twenty-four subjects were classified as having secure attachment styles, 16 as nonsecure. The magnitude and predictability of parental investment during childhood was classified as lower if there was a brief intersibling interval, parental divorce, fewer economic resources, or less nurturing parents (i.e., more childhood adversity). Several such indicators were present for 17 people, 12 of whom were nonsecure, compared to only 4 of the 23 others. The nonsecurely attached subjects were less likely to have attained enduring marriages. The 6/16 nonsecure who had a marriage or cohabitation began them at a younger age and after a shorter courtship period than did the 15/24 secure with such relationships. Separations or divorces had already occurred in the relationships of 4/6 nonsecure versus 5/15 secure. Attachment security was associated with childhood adversity and adult relationships for both men and women, when analyzed separately. A retrospective study cannot address cause and effect, because poor adult relationship outcomes might bias recall of parental behavior. However, results are consistent with theories that unpredictable early environments foster short-term rather than long-term mating strategies, possibly through affecting attachment styles.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31362/1/0000274.pd

Diet at Late Chalcolithic Çamlıbel Tarlası, north-central Anatolia:An isotopic perspective

Carbon (δ13C) and nitrogen (δ15N) stable isotope analysis of bone collagen from 57 human and 137 faunal samples was conducted with the aim of reconstructing human diet at the Late Chalcolithic (mid-4th millennium BC) site of Çamlıbel Tarlası, north-central Anatolia. The analyses indicate that the diet of the inhabitants of Çamlıbel Tarlası was based largely on C3 resources. Comparison of human and faunal δ15N values suggest that animal proteins were likely to be of secondary importance to diet, with cultigens such as wheat and barley and potentially pulses taking the role of dietary staples. Age-related variation in stable isotope signals was identified

Burnt and Blossoming: Material Mysticism in Trilogy and Four Quartets

This paper brings two WWII poems into dialogue: H.D.'s Trilogy and Eliot's Four Quartets. Both poems express a creative response to the destruction of war. My reading of Trilogy suggests a material mysticism in which vision and renewal are situated within the natural world, rituals and bodily experience. Bringing this understanding of mysticism to bear on Four Quartets reveals tension between transcendence and materiality. For Eliot, redemption comes through time and location, while for H.D., redemption lies within material particularity. Four Quartets oscillates between an apophatic discourse that seeks to transcend desire and history and an emphasis on material particularities

COMPARE Forum: The idea of North-South and South-South collaboration

The idea of having a Compare Forum focusing on the above title was first discussed with one of the Editors of Compare during a PhD defence in Oslo in 2011. The PhD dissertation itself was linked to a larger project in which researchers from the North (Norway) and the South (South Africa) had been collaborating in educational research for over 10 years. Despite the fact that North-South collaboration is not a new issue on the agenda (King 1985) it is still a timely topic to explore, particularly given the recent growth and moves towards North-South-South collaboration or even South-South Cooperation in Education and Development (Chisholm and Steiner-Khamsi 2009). Thus, any discussion of research collaboration, whether North-South or South-South, is seen as an ideal topic for comparative education, particularly when exploring why there should be collaboration at all and if so what are some of the challenges. While it may be argued that the difference between North-South and South-South collaboration may simply be a question of geography, King (1985) reminds us that collaboration is not necessarily between equals and that collaboration at times ‘appears to be a process initiated in the North, and in which the South participates, as a counterpart’ (184). Ultimately, the differences go beyond simple geographic location to issues of funding and power, something that each of the contributions will touch upon in their own way. While cooperation may mean working with someone, it does suggest that one partner provides information or resources to the other, while collaboration suggests a more equal partnership in which researchers work alongside each other. For the majority of our contributors, we use collaboration as opposed to cooperation, although the literature is not always so clear on this distinction.Web of Scienc

Guidance on priority setting in health care (GPS-Health) : The inclusion of equity criteria not captured by cost-effectiveness analysis

This Guidance for Priority Setting in Health Care (GPS-Health), initiated by the World Health Organization, offers a comprehensive map of equity criteria that are relevant to health care priority setting and should be considered in addition to cost-effectiveness analysis. The guidance, in the form of a checklist, is especially targeted at decision makers who set priorities at national and sub-national levels, and those who interpret findings from cost-effectiveness analysis. It is also targeted at researchers conducting cost-effectiveness analysis to improve reporting of their results in the light of these other criteria. The guidance was develop through a series of expert consultation meetings and involved three steps: i) methods and normative concepts were identified through a systematic review; ii) the review findings were critically assessed in the expert consultation meetings which resulted in a draft checklist of normative criteria; iii) the checklist was validated though an extensive hearing process with input from a range of relevant stakeholders. The GPS-Health incorporates criteria related to the disease an intervention targets (severity of disease, capacity to benefit, and past health loss); characteristics of social groups an intervention targets (socioeconomic status, area of living, gender; race, ethnicity, religion and sexual orientation); and non-health consequences of an intervention (financial protection, economic productivity, and care for others)

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results