Identification and Validation of an Anthracycline/Cyclophosphamide–Based Chemotherapy Response Assay in Breast Cancer

Background: There is no method routinely used to predict response to anthracycline and cyclophosphamide–based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection.

Methods: DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided.

Results: In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population.

Conclusions: A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide–based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.

Risk and Reward: Safer systems of work practice.

To develop and implement a risk assessment process for all unlicenced medicinal products in use within the Belfast City Hospital.
Over half 65% of the unlicenced medicinal products currently in use were rated low or minor risk and therefore required no recording upon supply.
This has greatly improved the way unlicensed medicines are prescribed, procured, supplied and administered within the Belfast City Hospital.

A Randomized Controlled Trial Evaluation of an After-School Pro-Social Behavior Program in an Area of Socioeconomic Disadvantage

A randomized controlled trial was used to evaluate the effects of a pro-social behavior after-school program called Mate-Tricks for nine and ten year old children and their parents living in an area of significant socioeconomic disadvantage. The children were randomly assigned to an intervention (n=220) or a control group (n=198). Children were compared on measures of pro-social behavior, anti-social behavior and related outcome measures. The trial found adverse effects on four outcomes among the intervention group compared to the control group: anti-social behavior increased on two different measures (d=+0.20) and (d=+0.18); child reported liberal parenting increased (d=+0.16); and child reported authoritarian parenting also increased (d=+0.20). In addition, parental participation was significantly associated with several program outcomes. It was concluded, that group based after-school behavior programs may have the potential to cause iatrogenic effects and must be designed, piloted, evaluated and implemented with a high degree of care.

A realist literature review of transition to adult services by young people with life-limiting conditions in ireland.

Background As a result of improvements in care and treatment more young people with life-limiting conditions are now living beyond childhood, meaning they must make the transition from children's to adult services. The loss of long-standing relationships with providers of children's services combines with poor co-ordination of services to make this a daunting prospect for young people and their families. However, there is little evidence on transition services for young people with life limiting conditions, with few models of good practice in the literature.


Aims The purpose of this review was to determine the factors that promote or hinder the transition to adult services for young adults with life limiting conditions, and identify gaps to be addressed.


Methods A comprehensive search of the literature was undertaken using key terms, of the following databases; MEDLINE and the Cochrane Database of Systematic Reviews. 314 articles were sourced and inclusion and exclusion criteria were applied to highlight the most relevant literature.


Results Studies were reviewed using a realist review approach and three themes emerged from the literature. Barriers and facilitators to the transition process were identified associated with: 1. The patient 2. Parents/carers 3. The organisation.


Conclusion It is unclear from the literature what the specific factors are that promote or hinder the transition process for young adults with life limiting conditions who go through the transition from children's to adult services, therefore, research is required to identify the factors that promote and hinder the transition process in Ireland. This research is currently being carried out by the author as part of Doctoral studies. The three year full time Doctoral study commenced in January 2013 and is funded by the All Ireland Institute of Hospice and Palliative Care.

The radiated energy budget of Chromospheric Plasma in a major solar flare deduced from multi-wavelength observations

This paper presents measurements of the energy radiated by the lower solar atmosphere, at optical, UV, and EUV wavelengths, during an X-class solar flare (SOL2011-02-15T01:56) in response to an injection of energy assumed to be in the form of nonthermal electrons. Hard X-ray observations from RHESSI were used to track the evolution of the parameters of the nonthermal electron distribution to reveal the total power contained in flare accelerated electrons. By integrating over the duration of the impulsive phase, the total energy contained in the nonthermal electrons was found to be >2 × 1031 erg. The response of the lower solar atmosphere was measured in the free–bound EUV continua of H i (Lyman), He i, and He ii, plus the emission lines of He ii at 304 Å and H i (Lyα) at 1216 Å by SDO/EVE, the UV continua at 1600 Å and 1700 Å by SDO/AIA, and the white light continuum at 4504 Å, 5550 Å, and 6684 Å, along with the Ca ii H line at 3968 Å using Hinode/SOT. The summed energy detected by these instruments amounted to ~3 × 1030 erg; about 15% of the total nonthermal energy. The Lyα line was found to dominate the measured radiative losses. Parameters of both the driving electron distribution and the resulting chromospheric response are presented in detail to encourage the numerical modeling of flare heating for this event, to determine the depth of the solar atmosphere at which these line and continuum processes originate, and the mechanism(s) responsible for their generation.

Different frequencies of acupuncture for treatment for chronic low back pain: an-assessor blinded pilot randomised controlled trial.

OBJECTIVES:
To examine the feasibility of a main RCT to compare the effectiveness of two frequencies (2 versus 5 times/week) of acupuncture treatment for chronic low back pain (LBP).
METHODS:
Participants (n=30) with chronic LBP were randomised into two groups to receive 10 acupuncture treatments: Low Frequency Group, 2 times/week for five weeks (n=15); High Frequency Group, 5 times/week for two weeks (n=15). The following outcomes were measured blindly at baseline, 2 weeks, 5 weeks, 3 months and 1 year: pain on a VAS, functional disability using the RMDQ, quality of life using the Measure Yourself Medical Outcome Profile (MYMOP-2), psychological impact with the Coping Strategies Questionnaire (CSQ) and Pain Locus of Control (PLC) questionnaire. Two objective outcomes, the Shuttle Walk Test (SWT) and Lateral Trunk Flexibility (LTF), were also measured.
RESULTS:
The compliance rate was 100% for each group. Some of the measurements were shown to be sensitive (VAS, RMDQ, MYMOP-2 Wellbeing). 66-330 participants would be required for a fully powered non-inferiority trial. The groups were balanced at baseline for LBP and demographic characteristics. There were no significant differences between the groups in terms of any of the outcomes, at each follow-up time point. It was notable however that the clinically important improvement in terms of pain, functional disability, quality of life, and SWT in both groups was achieved within the first two weeks, which was maintained at one year follow-up.
CONCLUSIONS:
It is feasible to conduct a main RCT, to compare different frequencies of acupuncture for LBP, using sensitive measurements. Also the trend for early clinically important improvement within a minimum of four measurements is worthy of further study.

Dense spectrum of resonances and spin-1/2 particle capture in a near-black-hole metric

We show that a spin-1/2 particle in the gravitational field of a massive body of radius R which slightly exceeds the Schwarzschild radius rs, possesses a dense spectrum of narrow resonances. Their lifetimes and density tend to infinity in the limit R → rs. We determine the cross section of the particle capture into these resonances and show that it is equal to the spin-1/2 absorption cross section for a Schwarzschild black hole. Thus black-hole properties may emerge in a non-singular static metric prior to the formation of a black hole.

Transition from Children’s to Adult Services forYoung People with Life-limiting Conditions: Findings from a Questionnaire Survey in Northern Ireland

Research aims: 
To describe service provision for the transition from children’s to adult services for young people with life-limiting conditions in Northern Ireland, and to identify organisational factors that promote or inhibit effective transition. 
Study population: 
Health, social, educational and charitable organisations providing transition services to young people with life-limiting conditions in Northern Ireland. 
Study design and methods: 
A questionnaire has been developed by the research team drawing on examples from the literature and the advice of an expert advisory group. The questionnaire was piloted with clinicians,academics and researchers in June 2013. The questionnaire focuses on components of practice which may promote continuity in the transition from child to adult care for young people with a life-limiting condition. The survey will be distributed throughout Northern Ireland to an estimated 75 organisations, following the Dillman total design survey method. Numerical data will be analysed using PASW Statistical software to generate descriptive statistics along with a thematic analysis of data generated by open-ended questions. 
Results and interpretations: 
The survey will provide a description of services, transition policies, approaches to managing transition, categories of service users, the ages at which transition starts and completes, experiences with minority ethnic groups, the input of service users to the process, organisational factors promoting or hindering effective transition, links between services, and service providers’ recommendations for improvements in services.The outcomes will be an overview of the transition services currently provided in Northern Ireland identifying models of good practice and the key factors influencing the quality, safety and continuity of care. Survey results are due early in 2014.