Removing exogenous information using pedigree data

Management of certain populations requires the preservation of its pure genetic background. When, for different reasons, undesired alleles are introduced, the original genetic conformation must be recovered. The present study tested, through computer simulations, the power of recovery (the ability for removing the foreign information) from genealogical data. Simulated scenarios comprised different numbers of exogenous individuals taking partofthe founder population anddifferent numbers of unmanaged generations before the removal program started. Strategies were based on variables arising from classical pedigree analyses such as founders? contribution and partial coancestry. The ef?ciency of the different strategies was measured as the proportion of native genetic information remaining in the population. Consequences on the inbreeding and coancestry levels of the population were also evaluated. Minimisation of the exogenous founders? contributions was the most powerful method, removing the largest amount of genetic information in just one generation.However, as a side effect, it led to the highest values of inbreeding. Scenarios with a large amount of initial exogenous alleles (i.e. high percentage of non native founders), or many generations of mixing became very dif?cult to recover, pointing out the importance of being careful about introgression events in populatio

Long term geological record of a global deep subsurface microbial habitat in sand injection complexes

Peer reviewedPublisher PD

Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Assessing the feasibility, acceptability and potential effectiveness of Dignity Therapy for people with advanced cancer referred to a hospital-based palliative care team: Study protocol

<p>Abstract</p> <p>Background</p> <p>Loss of dignity for people with advanced cancer is associated with high levels of psychological and spiritual distress and the loss of the will to live. Dignity Therapy is a brief psychotherapy, which has been developed to help promote dignity and reduce distress. It comprises a recorded interview, which is transcribed, edited then returned to the patient, who can bequeath it to people of their choosing. Piloting in Canada, Australia and the USA, has suggested that Dignity Therapy is beneficial to people with advanced cancer and their families. The aims of this study are to assess the feasibility, acceptability and potential effectiveness of Dignity Therapy to reduce psychological and spiritual distress in people with advanced cancer who have been referred to hospital-based palliative care teams in the UK, and to pilot the methods for a Phase III RCT.</p> <p>Design</p> <p>A randomised controlled open-label trial. Forty patients with advanced cancer are randomly allocated to one of two groups: (i) Intervention (Dignity Therapy offered in addition to any standard care), and (ii) Control group (standard care). Recipients of the 'generativity' documents are asked their views on taking part in the study and the therapy. Both quantitative and qualitative outcomes are assessed in face-to-face interviews at baseline and at approximately one and four weeks after the intervention (equivalent in the control group). The primary outcome is patients' sense of dignity (potential effectiveness) assessed by the Patient Dignity Inventory. Secondary outcomes for patients include distress, hopefulness and quality of life. In view of the relatively small sample size, quantitative analyses are mainly descriptive. The qualitative analysis uses the Framework method.</p> <p>Discussion</p> <p>Dignity Therapy is brief, can be delivered at the bedside and may help both patients and their families. This detailed exploratory research shows if it is feasible to offer Dignity Therapy to patients with advanced cancer, many of whom are likely to be in the terminal stage of their illness, whether it is acceptable to them and their families, if it is likely to be effective, and determine whether a Phase III RCT is desirable.</p> <p>Trial registration</p> <p>Current Controlled Clinical Trials: ISRCTN29868352</p

Telomeric expression sites are highly conserved in trypanosoma brucei

Subtelomeric regions are often under-represented in genome sequences of eukaryotes. One of the best known examples of the use of telomere proximity for adaptive purposes are the bloodstream expression sites (BESs) of the African trypanosome Trypanosoma brucei. To enhance our understanding of BES structure and function in host adaptation and immune evasion, the BES repertoire from the Lister 427 strain of T. brucei were independently tagged and sequenced. BESs are polymorphic in size and structure but reveal a surprisingly conserved architecture in the context of extensive recombination. Very small BESs do exist and many functioning BESs do not contain the full complement of expression site associated genes (ESAGs). The consequences of duplicated or missing ESAGs, including ESAG9, a newly named ESAG12, and additional variant surface glycoprotein genes (VSGs) were evaluated by functional assays after BESs were tagged with a drug-resistance gene. Phylogenetic analysis of constituent ESAG families suggests that BESs are sequence mosaics and that extensive recombination has shaped the evolution of the BES repertoire. This work opens important perspectives in understanding the molecular mechanisms of antigenic variation, a widely used strategy for immune evasion in pathogens, and telomere biology

Exploring the effects of replicating shape, weight and recoil effects on VR shooting controllers

Commercial Virtual Reality (VR) controllers with realistic force feedback are becoming available, to increase the realism and immersion of first-person shooting (FPS) games in VR. These controllers attempt to mimic not only the shape and weight of real guns but also their recoil effects (linear force feedback parallel to the barrel, when the gun is shot). As these controllers become more popular and affordable, this paper investigates the actual effects that these properties (shape, weight, and especially directional force feedback) have on performance for general VR users (e.g. users with no marksmanship experience), drawing conclusions for both consumers and device manufacturers. We created a prototype replicating the properties exploited by commercial VR controllers (i.e. shape, weight and adjustable force feedback) and used it to assess the effect of these parameters in user performance, across a series of user studies. We first analysed the benefits on user performance of adding weight and shape vs a conventional controller (e.g. Vive controller). We then explore the implications of adding linear force feedback (LFF), as well as replicating the shape and weight. Our studies show negligible effects on the immediate shooting performance with some improvements in subjective appreciation, which are already present with low levels of LFF. While higher levels of LFF do not increase subjective appreciations any further, they lead users to reach their maximum distance skillset more quickly. This indicates that while adding low levels of LFF can be enough to influence user’s immersion/engagement for gaming contexts, controllers with higher levels of LFF might be better suited for training environments and/or when dealing with particularly demanding aiming tasks

Can We Really Prevent Suicide?

Every year, suicide is among the top 20 leading causes of death globally for all ages. Unfortunately, suicide is difficult to prevent, in large part because the prevalence of risk factors is high among the general population. In this review, clinical and psychological risk factors are examined and methods for suicide prevention are discussed. Prevention strategies found to be effective in suicide prevention include means restriction, responsible media coverage, and general public education, as well identification methods such as screening, gatekeeper training, and primary care physician education. Although the treatment for preventing suicide is difficult, follow-up that includes pharmacotherapy, psychotherapy, or both may be useful. However, prevention methods cannot be restricted to the individual. Community, social, and policy interventions will also be essentia

Moxibustion for cephalic version: a feasibility randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Moxibustion (a type of Chinese medicine which involves burning a herb close to the skin) has been used to correct a breech presentation. Evidence of effectiveness and safety from systematic reviews is encouraging although significant heterogeneity has been found among trials. We assessed the feasibility of conducting a randomised controlled trial of moxibustion plus usual care compared with usual care to promote cephalic version in women with a breech presentation, and examined the views of women and health care providers towards implementing a trial within an Australian context.</p> <p>Methods</p> <p>The study was undertaken at a public hospital in Newcastle, New South Wales, Australia. Women at 34-36.5 weeks of gestation with a singleton breech presentation (confirmed by ultrasound), were randomised to moxibustion plus usual care or usual care alone. The intervention was administered over 10 days. Clinical outcomes included cephalic presentation at birth, the need for ECV, mode of birth; perinatal morbidity and mortality, and maternal complications. Feasibility outcomes included: recruitment rate, acceptability, compliance and a sample size for a future study. Interviews were conducted with 19 midwives and obstetricians to examine the acceptability of moxibustion, and views on the trial.</p> <p>Results</p> <p>Twenty women were randomised to the trial. Fifty one percent of women approached accepted randomisation to the trial. A trend towards an increase in cephalic version at delivery (RR 5.0; 95% CI 0.7-35.5) was found for women receiving moxibustion compared with usual care. There was also a trend towards greater success with version following ECV. Two babies were admitted to the neonatal unit from the moxibustion group. Compliance with the moxibustion protocol was acceptable with no reported side effects. Clinicians expressed the need for research to establish the safety and efficacy of moxibustion, and support for the intervention was given to increase women's choices, and explore opportunities to normalise birth. The sample size for a future trial is estimated to be 381 women.</p> <p>Conclusion</p> <p>Our findings should be interpreted with caution as the study was underpowered to detect statistical differences between groups. Acceptance by women and health professionals towards moxibustion suggest further research is warranted.</p> <p>Trial Registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12609000985280.aspx">ACTRN12609000985280</a></p

Recent trends in cutaneous malignant melanoma in the Yorkshire region of England; incidence, mortality and survival in relation to stage of disease, 1993–2003

The aim of this study was to investigate recent trends in incidence, mortality and survival in patients diagnosed with malignant melanoma (MM) in relation to stage (Breslow thickness). Cases of primary invasive and in situ MM diagnosed between 1st January 1993 and 31st December 2003 in the former Yorkshire Health Authority were identified from cancer registry data. Over the study period, the incidence of invasive MM increased from 5.4 to 9.7 per 100 000 in male subjects and from 7.5 to 13.1 per 100 000 in female subjects. Most of this increase was seen in thin tumours (<1.5 mm). Thin tumours were more likely to be diagnosed in the younger age groups and be classified as superficial spreading melanoma. In situ melanoma rates increased only slightly. Over the same time period, mortality rates have been relatively constant in both male and female subjects. Five-year relative survival varied from 91.8% (95% CI 90.4–93.1) for patients with thin tumours to 41.5% (95% CI 36.7–46.3) for those with thick tumours. In multivariable analyses, Breslow thickness was the most important prognostic factor. Age, sex and level of deprivation were also identified as independent prognostic factors. The trends in incidence suggest that the increase is real, rather than an artefact of increased scrutiny, implying that primary prevention in the Yorkshire area of the UK has failed to control trends in incidence. Mortality, in contrast, appears to be levelling off, indicating that secondary prevention has been more effective