Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Background: Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.

Methods: COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.

Findings: We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).

Interpretation: Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

Children drawing their own conclusions: Children’s perceptions of a ‘post-conflict’ society

In societies emerging from conflict/war, sustained occurrence of violence appears to be a common feature. In Northern Ireland, while incidents of violent deaths and injuries specifically related to the political conflict have decreased dramatically since 1998, regular riots and paramilitary activity confirm continuing division and conflict. The study described here explored children’s perceptions of their own lives and their predecessors’ lives in the country, through a draw-and-tell technique (n=179). While multiple positive elements of peace/hope were depicted by the majority of children, especially in the pictures portraying the present, negative elements and violent references mostly appeared in the pictures representing the past. Violence was more likely to be portrayed by boys, older children, and those attending segregated education.

Psychological responses after a major fatal earthquake: The effect of preitraumatic dissociation and posttraumatic stress symptoms on anxiety and depression.

Following trauma, most people with initial symptoms of stress recover, but it is important to identify those at risk for continuing difficulties so resources are allocated appropriately. There has been limited investigation of predictors of posttraumatic stress disorder following natural disasters. This study assessed psychological difficulties experienced in 101 adult treatment seekers following exposure to a significant earthquake. Peritraumatic dissociation, posttraumatic stress symptoms, anxiety, depression, and emotional support were assessed. Path analysis was used to determine whether the experience of some psychological difficulties predicted the experience of other difficulties. As hypothesized, peritraumatic dissociation was found to predict posttraumatic stress symptoms and anxiety. Posttraumatic stress symptoms then predicted anxiety and depression. Depression and anxiety were highly correlated. Contrary to expectations, emotional support was not significantly related to other psychological variables. These findings justify the provision of psychological support following a natural disaster and suggest the benefit of assessing peritraumatic dissociation and posttraumatic stress symptoms soon after the event to identify people in need of monitoring and intervention.

Day case stapled haemorrhoidopexy for prolapsing haemorrhoids

Objective Conventional surgical management of prolapsing haemorrhoids is by excisional haemorrhoidectomy. Postoperative pain has restricted the application of such procedures in the day case setting. These operations remain associated with a period of restricted activity. The use of circular stapling devices as an alternative to the excisional approach in the management of haemorrhoids has been described. This study reports our experience of stapled haemorrhoidopexy as a day case procedure.

Methods Patients with third or fourth degree haemorrhoids were eligible for the procedure. Patients were considered suitable candidates for day case surgery based on conventional parameters. Symptoms were assessed using a previously validated symptom severity rating score. Stapled haemorrhoiclopexy was carried out using a circular stapling device. Pain scores were obtained prior to discharge. Patients were admitted if pain was uncontrolled despite oral analgesia. Symptoms were re-scored at six-week follow-up.

Results Over a 70-month period 168 consecutive stapled haemorrhoidopexies were performed or directly supervised by one consultant colorectal surgeon. One hundred and ten (65%) patients were considered appropriate candidates for day case surgery by conventional criteria. Ninety-six (87.3%) patients successfully underwent stapled haemorrhoidopexyon a day case basis. Fourteen (12.7%) patients required admission on the day of surgery (5 for early Postoperative bleeding, 4 for pain necessitating continuing opiate analgesia, two for urinary retention and three for surgery performed late in the day). Six (5%) patients were re-admitted postoperatively; four for pain relief and two because of urinary retention. Of the day case patients, 91 (82.7%) and 56 (50.9%) had been seen for 6 week and 6 month review, respectively, at the time of analysis. Symptom scores were 6 (pre-operatively) vs 0 (postoperatively) (P <0.01). 76/91 (83.5%) patients reviewed at 6/52 were asymptomatic.

Conclusion Stapled haemorrhoidopexy is a safe and effective procedure that can be carried out on selected patients on a day case basis. Complications are of a similar nature to excisional haemorrhoidectomy.

Resistance is Feral: Digital Culture, Community Arts, and the New Cultural Gatekeepers

The Community Arts sector in Australia has a history of resistance. It has challenged hegemonic culture through facilitating grassroots creative production, contesting notions of artistic processes, and the role of the artist in society. This paper examines this penchant for resistance through the lens of contemporary digital culture, to establish that the sector is continuing to challenge dominant forms of cultural control. It then proposes that this enthusiasm and activity lacks ethical direction, describing it as feral to encompass the potential of current practices, while highlighting how a level of taming is needed in order to develop ethical approaches.

Women’s Perceptions and Experiences of Fetal Macrosomia

Objective
to explore women's perceptions and experiences of pregnancy and childbirth following birth of a macrosomic infant (birth weight ≥4000 g).

Methods
a qualitative design utilising interviews conducted 13–19 weeks post partum in women's homes. The study was conducted in one Health and Social Care Trust in Northern Ireland between January and September 2010. Participants were identified from a larger cohort of women recruited to a prospective study exploring the impact of physical activity and nutrition on macrosomia. Eleven women who delivered macrosomic infants participated in this phase of the study.

Findings
four overarching themes emerged: preparation for delivery; physical and emotional impact of macrosomia; professional relations and perceptions of macrosomia. Findings highlighted the importance of communication with health professionals in relation to both prediction of macrosomia and decision making about childbirth, and offers further understanding into the physical and emotional impact of having a macrosomic infant on women. Furthermore, there was evidence that beliefs and perceptions relating to macrosomia may influence birth experiences and uptake of health promotion messages.

Key conclusions and implications for practice
this study provides important insight into women's experiences of macrosomia throughout the perinatal period and how they were influenced by previous birth experiences, professional relations and personal perceptions and beliefs about macrosomia. Pregnant women at risk of having a macrosomic infant may require extra support throughout the antenatal period continuing into the postnatal period. Support needs to be tailored to the woman's information needs, with time allocated to explore previous birth experiences, beliefs about macrosomia and options for childbirth.

Famine and land, 1845-80

While historians once tended to displace the Famine from a pivotal position in modern Irish history, more recent research emphasizes its centrality, and focuses upon the controversial issue of state responsibility. Mortality levels from the Famine place it, proportionately, as one of the most devastating recorded human catastrophes. Official British policy towards Ireland spanned two governments, those of Robert Peel and John Russell, with historians taking a more emollient view of the former: in fact there were significant continuities between the two. The legacy of the Famine was uneven, with commercial and technological advance and the consolidation of both the farming interest and landlordism. On the other hand, recent research emphasizes evidence of continuing economic uncertainty, particularly in the West, together with ongoing landlord-tenant tensions. Rural insecurities, crystallized by the poor harvests of 185964, underlay the post-Famine years, and fed into the politicization of the later 1870s.

Editorial- Environmental Tracers

Environmental tracers continue to provide an important tool for understanding the source, flow and mixing dynamics of water resource systems through their imprint on the system or their sensitivity to alteration within it. However, 60 years or so after the first isotopic tracer studies were applied to hydrology, the use of isotopes and other environmental tracers are still not routinely necessarily applied in hydrogeological and water resources investigations where appropriate. There is therefore a continuing need to promote their use for developing sustainable management policies for the protection of water resources and the aquatic environment. This Special Issue focuses on the robustness or fitness-for-purpose of the application and use of environmental tracers in addressing problems and opportunities scientifically, to promote their wider use and to address substantive issues of vulnerability, sustainability, and uncertainty in (ground)water resources systems and their management.

At Home in Care: Children living with birth parents on a Care Order

This study explored the processes, background information, and perceived reasons why children and young people returned home while remaining in care, in the five HSC Trusts in Northern Ireland. The research also focused on understanding the functions the Care Order had for social services, the birth parents, and young people involved.
It was found that on 31st March 2009, there were 193 children/young people living with their birth parents on a Care Order in Northern Ireland. This is eight per cent of the total population of Looked After children, and is lower than had been anticipated from governmental statistics. In total, the case files of 47 of these young people (24% of them) were reviewed, and interviews were conducted with ten of them and their birth parent/s.
The analysis revealed that the majority of them had in common a parental background history of alcohol abuse and domestic violence, and most return breakdowns in the study were related to continuing parental alcohol and/or drugs misuse. While some children had a planned return home after parents had engaged in supports and completed assessments, many young people had returns that were not planned, as they initiated the move themselves, or previous foster placements had broken down and there were no alternative placements identified for them. Many of these young people essentially ‘voted with their feet’, and social services were required to ensure that they remained safe in often less than optimal circumstances.
After returning home, for many, Care Orders remained for initially unintended lengthy periods because of the risks posed by parents’ intermittent alcohol abuse and their lifestyle, contact issues, and parents’ desire to ensure that their children were able to access the supports that they needed. Thus, Care Orders at home tended to serve two main functions: to either monitor and/or support the placement.

The G20 and Monetary Policy Stasis

Since the financial crash of 2008 monetary policy has been in a state of stasis – a condition in which things are not changing, moving, or progressing, but rather appear frozen. Interest rates have been frozen at low levels for a considerable period time. Inflation targets have consistently been missed, through phases of both overshooting and undershooting. At the same time, a variety of unconventional monetary policies involving asset purchases and liquidity provision have been pursued. Questions have been raised from a variety of sources, including various international organizations, covering distinct BIS and IMF positions about the continuing validity and sustainability of existing monetary policy frameworks, not least because inflation targeting has ceased to act as reliable guide for policy for over six years. Despite this central banks have been reluctant to debate moving to a new formal policy framework. This article argues that as an apex policy forum only the G20 leaders’ summits has the necessary political authority to call their central banks to account and initiate a wide ranging debate on the future of monetary policy. A case is made for convening a monetary policy working group to discuss a range of positions, including those of the BIS and IMF, and to make recommendations, because the G20 has been most effective in displaying international financial leadership, when leaders have convened and made use of specialist working groups.

Air pollutant contamination and acidification of surface waters in the North York Moors, UK: Multi-proxy evidence from the sediments of a moorland pool

Despite the extensive geographical range of palaeolimnological studies designed to assess the extent of surface water acidification in the United Kingdom during the 1980s, little attention was paid to the status of surface waters in the North York Moors (NYM). In this paper, we present sediment core data from a moorland pool in the NYM that provide a record of air pollution contamination and surface water acidification. The 41-cm-long core was divided into three lithostratigraphic units. The lower two comprise peaty soils and peats, respectively, that date to between approximately 8080 and 6740 cal. BP. The uppermost unit comprises peaty lake muds dating from between approximately ad 1790 and the present day (ad 2006). The lower two units contain pollen dominated by forest taxa, whereas the uppermost unit contains pollen indicative of open landscape conditions similar to those of the present. Heavy metal, spheroidal carbonaceous particle, mineral magnetics and stable isotope analysis of the upper sediments show clear evidence of contamination by air pollutants derived from fossil-fuel combustion over the last c. 150years, and diatom analysis indicates that the naturally acidic pool became more acidic during the 20th century. We conclude that the exceptionally acidic surface waters of the pool at present (pH=c. 4.1) are the result of a long history of air pollution and not because of naturally acidic local conditions. We argue that the highly acidic surface waters elsewhere in the NYM are similarly acidified and that the lack of evidence of significant recovery from acidification, despite major reductions in the emissions of acidic gases that have taken place over the last c. 30years, indicates the continuing influence of pollutant sulphur stored in catchment peats, a legacy of over 150years of acid deposition.

Boys' underachievement, educational aspirations and constructions of locality

Over recent years the moral panic that has surrounded 'boys' underachievement' has tended to encourage crude and essentialist comparisons between all boys and all girls and to eclipse the continuing and more profound effects on educational achievement exerted by social class and 'race'/ethnicity. While there are differences in educational achievement between working class boys and girls, these differences are relatively minor when comparing the overall achievement levels of working class children with those from higher, professional social class backgrounds. This paper argues that a need exists therefore for researchers to fully contextualise the gender differences that exist in educational achievement within the over-riding contexts provided by social class and 'race'/ethnicity. The paper provides an example of how this can be done through a case study of 11-year-old children from a Catholic, working class area in Belfast. The paper shows how the children's general educational aspirations are significantly mediated by their experiences of the local area in which they live. However, the way in which the children come to experience and construct a sense of locality differs between the boys and girls and this, it is argued, helps to explain the more positive educational aspirations held by some of the girls compared to the boys. The paper concludes by considering the relevance of locality for understanding its effects on educational aspirations among other working class and/or minority ethnic communities.

Cross-age tutoring in kindergarten and elementary school settings: a systmeatic review and meta-analysis

Background: Qualified teaching staffs are neither available nor affordable to provide large numbers of children with individual attention. One solution to providing individual tuition has been the development of tutoring programs that are delivered by nonprofessional tutors, such as classmates, older children and community volunteers. Objectives: We have conducted a systematic review of cross-age tutoring interventions delivered by non-professional tutors to children between 5 and 11 years old. Only randomized controlled trials with reliable measures of academic outcomes, and continuing for at least 12 weeks, compared to instruction as usual, were included. Results: Searches of electronic databases and previous reviews, and contacts with researchers yielded 11,564 titles; after screening, 15 studies were included in the analysis. Cross-age tutoring showed small significant effects for tutees on the composite measure of reading (g=0.18, 95% CI: 0.08, 0.27, N=8251), decoding skills (g=0.29, 95% CI: 0.13, 0.44, N=7081), and reading comprehension (g=0.11, 95% CI: 0.01, 0.21, N=6945). No significant effects were detected for other reading sub-skills or for mathematics. The quality of evidence is decreased by study limitations and high heterogeneity of effects. Conclusions: The benefits for tutees of non-professional peer and cross-age tutoring can be given a positive but weak recommendation, considering the low quality of evidence and lack of cost information. Subgroup analyses suggested that highly-structured reading programs may be more useful than loosely-structured programs. Large-scale replication trials using factorial design, process evaluations, reliable outcome measures and logic models are needed to better understand under what conditions, and for whom, cross-age non-professional tutoring may be effective.

Optical Spectroscopy of Unbound Asteroid Pairs

The recently discovered unbound asteroid pairs have been suggested to be the result of the decoupling of binary asteroids formed either through collision processes or, more likely, rotational fission of a rubble-pile asteroid after spin-up (Vokrouhlicky et al. 2008, AJ 136, 280; Pravec et al., 2010, Nature, 466, 1085). Much of the evidence for linkage of the asteroids in each pair relies solely on the backwards integrations of their orbits. We report new results from our continuing spectroscopic survey of the unbound asteroid pairs, including the youngest known pair, (6070) Rhineland - (54827) 2001 NQ8. The survey goal is to determine whether the asteroids in each unbound pair have similar spectra and therefore composition, expected if they have formed from a common parent body. Low-resolution spectroscopy covering the range 0.4-0.95 microns was conducted using the 3.6m ESO NTT+EFOSC2 during 2011-2012 and the 4.2m WHT+ACAM. We have attempted to maintain a high level of consistency between the observations of the components in each pair to ensure that differences in the asteroid spectra are not the result of the observing method or data reduction, but purely caused by compositional differences. Our WHT data indicates that the asteroids of unbound pair 17198 - 229056 exhibit different spectra and have been assigned different taxonomies, A and R respectively. Initial analysis of our data from the NTT suggests that the asteroids in unbound pairs 6070 - 54827 and 38707 - 32957 are likely silicate-dominated asteroids. The components of pair 23998 - 205383 are potentially X-type asteroids. We present final taxonomic classifications and the likelihood of spectral similarity in each pair.

"The Constitution in Northern Ireland - After the Scottish Independence Referendum"

This chronicle considers some of the possible developments in the Northern Ireland Peace Process that may be occasioned by the imperatives for wider constitutional change resulting from the Independence Referendum in Scotland in September 2014. After reviewing the devolution story in Scotland, and the developments leading to the referendum, some of the wider tensions that remain within the UK constitution are reviewed, and their impact on the Northern Ireland settlement are considered. Next, attention is given to the range of issues that are presently undermining the continuing success of the Northern Ireland settlement as a mechanism of government and the possibilities for adapting the constitutional architecture to overcome these difficulties.