Persistent donor chimaerism is consistent with disease-free survival following BMT for chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) can be treated successfully with allogeneic bone marrow transplantation (BMT) leading to long-term disease-free survival. Leukemia relapse, however, remains a significant clinical problem. Relapse following BMT presumably results from the expansion of small numbers of recipient leukaemic cells which have survived the conditioning therapy. In order to define patients who are at a high risk of leukaemia relapse, a variety of techniques have been employed to detect persistence of host haemopoiesis (mixed chimaerism, MC) or residual leukaemia (minimal residual disease, MRD). However, the precise relationship between the detection of MC and MRD post-BMT is unknown. We have investigated chimaerism and MRD status in 22 patients who were in clinical and haematological remission post-allogeneic BMT for chronic phase CML. Chimaerism was assessed using short tandem repeat PCR (STR-PCR) while BCR-ABL mRNA detection using reverse transcriptase polymerase chain reaction (RT-PCR) was performed to detect the presence of MRD. Seventeen patients received unmanipulated marrow (non-TCD) while in five patients a T cell-depleted transplant (TCD) was performed as additional GVHD prophylaxis. Chimaerism was evaluated in 18 patients (14 non-TCD, four TCD). Mixed chimaerism was an uncommon finding in recipients of unmanipulated BMT (21%) when compared to TCD BMT (100%). No evidence of MRD, as identified using the BCR-ABL mRNA RT-PCR assay, was detected in those patients who were donor chimaeras. Early and transient MC and MRD was detected in four patients (two non-TCD, two TCD) who have subsequently converted to a donor profile. One patient has stable low-level MC but remains MRD negative 4 years post-BMT. Late MC and MRD was observed in two patients who relapsed >6 years after TCD BMT for CML. We conclude that mixed chimaerism is a rare event in recipients of unmanipulated BMT and that donor chimaerism as detected by STR-PCR assay is consistent with disease-free survival and identifies patients with a low risk of leukaemic relapse post-BMT for CML.

Donor chimaerism is a strong indicator of disease free survival following bone marrow transplantation for chronic myeloid leukaemia

Although Chronic Myeloid Leukaemia (CML) can be treated successfully with allogeneic bone marrow transplantation (BMT), leukaemia relapse remains a significant clinical problem. Molecular monitoring of the post transplant marrow can be useful in predicting relapse particularly in CML patients where the Philadelphia chromosome or its molecular counterpart, the BCR-ABL fusion messenger RNA can be used as a leukaemia specific marker of minimal residual disease (MRD). We have investigated chimaerism (using polymerase chain reaction of short tandem repeat sequences (STR-PCR)) and MRD status (using reverse transcriptase PCR of the BCR-ABL fusion mRNA) in a serial fashion in 18 patients who were in clinical and haematological remission post allogeneic BMT for chronic phase CML. Eleven patients exhibited complete donor chimaerism with no evidence of minimal residual disease. Five patients had transient or low level stable MC. Late MC and MRD was observed in two patients who relapsed > 6 years after T cell depleted BMT for CML. Thus STR-PCR is an appropriate screening test in the post transplant setting for CML patients, but those patients exhibiting mixed haemopoietic chimaerism should also be monitored using a leukaemia specific sensitive molecular assay.

Impact of Free Glasses and a Teacher Incentive on Children's Use of Eyeglasses: A Cluster-Randomized Controlled Trial.

Purpose: To study the effect of free glasses combined with teacher incentives on in-school glasses wear among Chinese urban migrant children. Design: Cluster-randomized controlled trial. Methods: Children with VA <= 6/12 in either eye due to refractive error in 94 randomly-chosen primary schools underwent randomization by school to receive free glasses, education on their use and a teacher incentive (Intervention), or glasses prescriptions only (Control). Intervention group teachers received a tablet computer if >= 80% of children given glasses wore them during un-announced visits 6 weeks and 6 months (main outcome) after intervention. Results: Among 4376 children, 728 (16.7%, mean age 10.9 years, 51.0% boys) met enrollment criteria and were randomly allocated, 358 (49.2%, 47 schools) to Intervention and 370 (50.8%, 47 schools) to Control. Among these, 693 children (95.2%) completed the study and underwent analysis. Spectacle wear was significantly higher at 6 months among Intervention children (Observed [main outcome]: 68.3% versus 23.9%, Adjusted Odds Ratio [OR]=11.5, 95% Confidence Interval [CI] 5.91-22.5, P<0.001; Self-reported: 90.6% versus 32.1%, OR = 43.7, 95% CI = 21.7-88.5, P < 0.001). Other predictors of observed wear at 6 months included baseline spectacle wear (P<0.001), uncorrected VA<6/18 (P=0.01) and parental spectacle wear (P=0.02). The 6-month observed wear rate was only 41% among similar-aged children provided free glasses in our previous trial without teacher incentives. Conclusions: Free spectacles and teacher incentives maintain classroom wear in the large majority of children needing glasses over a school year. Low wear among Control children demonstrates the need for interventions.

Element-Free Galerkin Modelling of Crack Migration in Composite Laminates

The development of a virtual testing environment, as a cost-effective industrial design tool in the design and analysis of composite structures, requires the need to create models efficiently, as well as accelerate the analysis by reducing the number of degrees of freedom, while still satisfying the need for accurately tracking the evolution of a debond, delamination or crack front. The eventual aim is to simulate both damage initiation and propagation in components with realistic geometrical features, where crack propagation paths are not trivial. Meshless approaches, and the Element-Free Galerkin (EFG) method, are particularly suitable for problems involving changes in topology and have been successfully applied to simulate damage in homogeneous materials and concrete. In this work, the method is utilized to model initiation and mixed-mode propagation of cracks in composite laminates, and to simulate experimentally-observed crack migration which is difficult to model using standard finite element analysis. N

Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the STAMPEDE Trial

Importance: The natural history of patients with newly diagnosed high-risk nonmetastatic (M0) prostate cancer receiving hormone therapy (HT) either alone or with standard-of-care radiotherapy (RT) is not well documented. Furthermore, no clinical trial has assessed the role of RT in patients with node-positive (N+) M0 disease. The STAMPEDE Trial includes such individuals, allowing an exploratory multivariate analysis of the impact of radical RT.

Objective: To describe survival and the impact on failure-free survival of RT by nodal involvement in these patients.

Design, Setting, and Participants: Cohort study using data collected for patients allocated to the control arm (standard-of-care only) of the STAMPEDE Trial between October 5, 2005, and May 1, 2014. Outcomes are presented as hazard ratios (HRs) with 95% CIs derived from adjusted Cox models; survival estimates are reported at 2 and 5 years. Participants were high-risk, hormone-naive patients with newly diagnosed M0 prostate cancer starting long-term HT for the first time. Radiotherapy is encouraged in this group, but mandated for patients with node-negative (N0) M0 disease only since November 2011.

Exposures: Long-term HT either alone or with RT, as per local standard. Planned RT use was recorded at entry.

Main Outcomes and Measures: Failure-free survival (FFS) and overall survival.

Results: A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range [IQR], 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months' median follow-up. Two-year survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 [95% CI, 1.46-2.81]) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29-0.79]).

Conclusions and Relevance: Survival for men entering the cohort with high-risk M0 disease was higher than anticipated at study inception. These nonrandomized data were consistent with previous trials that support routine use of RT with HT in patients with N0M0 disease. Additionally, the data suggest that the benefits of RT extend to men with N+M0 disease.

Trial Registration: clinicaltrials.gov Identifier: NCT00268476; ISRCTN78818544.

Carbon Sink Conservation and Global Justice: Benefiting, Free Riding and Non-Compliance

It is often assumed that in order to avoid the most severe consequences of global anthropogenic climate change we have to preserve our existing carbon sinks, such as for instance tropical forests. Global carbon sink conservation raises a host of normative issues, though, since it is debatable who should pay the costs of carbon sink conservation, who has the duty to protect which sinks, and how far the duty to conserve one’s carbon sinks actually extends, especially if it conflicts with other duties one might have. According to some, forested states like Ecuador have a duty to preserve their tropical forests while the rich states of the global North have a duty of fairness to compensate states like Ecuador for the costs they incur. My aim in this paper is to critically analyse this standard line of argument and to criticise its validity both internally (i.e. with regard to its normative conclusion based on its premises) and externally (i.e. with regard to the argument’s underlying assumptions and its lack of contextualisation). As I will argue, the duty to conserve one’s forests is only a particular instantiation of a wider, more general duty to contribute towards global climate justice for which the context in which one operates (e.g. whether other agents are complying with their duties of global climate justice or not) matters significantly.

Behaviour-time budget and functional habitat use of a free-ranging European badger (Meles meles)

Background: The European badger (Melesmeles) is involved in the maintenance of bovine tuberculosis infection and onward spread to cattle. However, little is known about how transmission occurs. One possible route could be through direct contact between infected badgers and cattle. It is also possible that indirect contact between cattle and infected badger excretory products such as faeces or urine may occur either on pasture or within and around farm buildings. A better understanding of behaviour patterns in wild badgers may help to develop biosecurity measures to minimise direct and indirect contact between badgers and cattle. However, monitoring the behaviour of free-ranging badgers can be logistically challenging and labour intensive due to their nocturnal and semi-fossorial nature.We trialled a GPS and tri-axial accelerometer-equipped collar on a free-ranging badger to assess its potential value to elucidate behaviour-time budgets and functional habitat use. Results: During the recording period between 16:00 and 08:00 on a single night, resting was the most commonly identified behaviour (67.4%) followed by walking (20.9%), snuffling (9.5%) and trotting (2.3%).When examining accelerometer data associated with each GPS fix and habitat type (occurring 2 min 30 s before and after), walking was themost common behaviour in woodland (40.3%) and arable habitats (53.8%), while snuffling was themost common behaviour in pasture (61.9%). Several nocturnal resting periods were also observed. The total distance travelled was 2.28 km. Conclusions: In the present report, we demonstrate proof of principle in the application of a combined GPS and accelerometer device to collect detailed quantitative data on wild badger behaviour. Behaviour-time budgets allow us to investigate how badgers allocate energy to different activities and how thismight change with disease status. Such information could be useful in the development of measures to reduce opportunities for onward transmission of bovine tuberculosis from badgers to cattle.

Reversal in gender valuations of cataract surgery after the implementation of free screening and low-priced high-quality surgery in a rural population of southern China.

PURPOSE: To assess the impact of community outreach and the availability of low-cost surgeries [500 Renminbi (RMB) or 65 United States dollars (US$) per surgery] on the willingness to pay for cataract surgery among male and female rural-dwelling Chinese.METHODS: Cross-sectional willingness-to-pay surveys were conducted at the initiation of a cataract outreach programme in June 2001 and then again in July 2006. Respondents underwent visual acuity testing and provided socio-demographic data.RESULTS: In 2001 and 2006, 325 and 303 subjects, respectively, were interviewed. On average the 2006 sample subjects were of similar age, more likely to be female (p < 0.01), illiterate (p < 0.01), and less likely to come from a household with annual income of less than US$789 (62% vs. 87%, p < 0.01). Familiarity with cataract surgery increased from 21.2% to 44.4% over the 5 years for male subjects (p < 0.01) and 15.8%-44.4% among females (p < 0.01). The proportion of respondents willing to pay at least 500 RMB for surgery increased from 67% to 88% (p < 0.01) among male subjects and from 50% to 91% (p < 0.01) among females.CONCLUSIONS: Five years of access to free cataract testing and low-cost surgery programmes appears to have improved the familiarity with cataract surgery and increased the willingness to pay at least 500 RMB (US$65) for it in this rural population. Elderly women are now as likely as men to be willing to pay at least 500 RMB, reversing gender differences present 5 years ago.