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Survival of the African trypanosome within its mammalian hosts, and hence transmission between hosts, relies upon antigenic variation, where stochastic changes in the composition of their protective variant-surface glycoprotein (VSG) coat thwart effective removal of the pathogen by adaptive immunity. Antigenic variation has evolved remarkable mechanistic complexity in Trypanosoma brucei , with switching of the VSG coat executed by either transcriptional or recombination reactions. In the former, a single T. brucei cell selectively transcribes one telomeric VSG transcription site, termed the expression site (ES), from a pool of around 15. Silencing of the active ES and activation of one previously silent ES can lead to a co-ordinated VSG coat switch. Outside the ESs, the T. brucei genome contains an enormous archive of silent VSG genes and pseudogenes, which can be recombined into the ES to execute a coat switch. Most such recombination involves gene conversion, including copying of a complete VSG and more complex reactions where novel 'mosaic' VSG s are formed as patchworks of sequences from several silent (pseudo)genes. Understanding of the cellular machinery that directs transcriptional and recombination VSG switching is growing rapidly and the emerging picture is of the use of proteins, complexes and pathways that are not limited to trypanosomes, but are shared across the wider grouping of kinetoplastids and beyond, suggesting co-option of widely used, core cellular reactions. We will review what is known about the machinery of antigenic variation and discuss if there remains the possibility of trypanosome adaptations, or even trypanosome-specific machineries, that might offer opportunities to impair this crucial parasite-survival process. • African trypanosomes evade host immune defences by stochastically switching the Variant Surface Glycoprotein (VSG) expressed on their surface, a process called antigenic variation. • African trypanosomes co-opt widely conserved factors and processes to coordinate switching events, and possibly monogenic antigen expression. • The wide conservation of these reactions may hinder the development of anti-trypanocidal drugs targeting antigenic variation. • VSG switching by recombination potentially involves a number of DNA break repair reactions, initiated by lesions within the telomeric sites of VSG transcription. • The spatial integration of transcription and splicing shapes a specific and critical nuclear organisation to sustain VSG monogenic expression and boost RNA processing. [ABSTRACT FROM AUTHOR]

Patients with substance-use disorder and pain are at risk of having their pain underestimated and undertreated. Unrelieved pain can exacerbate characteristics that are believed to be ‘drug-seeking’ and in turn, perceived drug-seeking behavior can contribute to a patient being stigmatized and labeled ‘difficult’. Previous literature has indicated that negative attitudes towards patients with substance-use disorder may affect their pain management but little is known about the specific barriers. This study explored nurses' experiences of working with patients with substance-use disorder in pain, providing an in-depth insight into their perspective. Descriptive phenomenology was employed as a framework for conducting semi-structured interviews to reveal the experiences of registered nurses. A convenience sample of registered nurses from a variety of clinical backgrounds were recruited and interviewed. This rich data was analyzed according to Giorgi's five-stage approach. Participants described feelings of powerlessness and frustration due to patient non-compliance, discrepancies in patient management amongst team members and external pressures effecting pain management. Participants described characteristics believed to be common, including psychosocial factors such as complex social backgrounds or mental health issues. Nurses' education and support needs were identified. Stereotyping and stigmatism were found to potentially still exist, yet there was also a general awareness of some specific clinical issues such as opioid tolerance and opioid-induced hyperalgesia. Further emphasis is required on interprofessional education and communication to improve patient management, alongside an appreciation of patient's rights facilitated by a concordance model of care. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: This paper reports on a phenomenological study of women's experiences 1–10 years following a radical vaginal trachelectomy and describes the impact on health, sexuality, fertility and perceived supportive care needs. Method and sample: Qualitative telephone interviews employing a descriptive phenomenological approach were conducted using a purposive sample of 12 women. Key results: Several felt their cancer experience was positive; bringing them closer to family and changed their outlook on life. A few experienced delayed psychological reactions and/or fears of recurrence. Many experienced isolation and the desire to contact others with similar experiences. Women recovered well but a few experienced fears/concerns about lymphoedema and intermenstrual bleeding. Sexual function was not a long-term issue for most. Some that could feel the cerclage (stitch) during intercourse, developed techniques to reduce this. Single women felt vulnerable in new relationships. Pregnancy was an anxious time, especially for those that experienced a miscarriage or pre-term birth. Sources of support included the clinical nurse specialist, family/friends, surgical consultant, online patient forums and a support group. Women needed more information on trachelectomy statistics, pregnancy care recommendations as well as access to counselling, peer support, being seen by the same person and increased public awareness. Conclusions: This study has provided an interesting and detailed insight into women's experiences in the years following a trachelectomy, with results that have important considerations for practice such as provision of statistical information; counselling; peer support; consistent pregnancy recommendations; increased public awareness and increased identification and management or prevention of long-term physical effects. [Copyright &y& Elsevier]

Abstract: Parkin-Smith GF, Norman IJ, Briggs E, Angier E, Wood TG, Brantingham JW. A structured protocol of evidence-based conservative care compared with usual care for acute nonspecific low back pain: a randomized clinical trial. Objective: To compare a protocol of evidence-based conservative care with usual care for acute nonspecific low back pain (LBP) of less than 6 weeks'' duration. Design: Parallel-group randomized trial. Setting: Three practices in the United Kingdom. Participants: Convenience sample of 149 eligible patients were invited to participate in the study, with 118 volunteers being consented and randomly allocated to a treatment group. Interventions: The experimental group received evidence-based treatments for acute nonspecific LBP as prescribed in a structured protocol of care developed for this study. The control group received usual conservative care. Participants in both groups could receive up to 7 treatments over a 4-week period. Main Outcome Measures: Oswestry Low Back Disability Index (ODI), visual analog scale (VAS), and Patient Satisfaction Questionnaire, alongside estimation of clinically meaningful outcomes. Results: Total dropout rate was 14% (n=16), with 13% of data missing. Missing data were replaced using a multiple imputation method. Participants in both groups received an average of 6 treatments. There was no statistically significant difference in disability (ODI) scores at the end of week 4 (P=.33), but there was for pain (VAS) scores (P<.001). Interestingly, there were statistically significant differences between the 2 groups for both disability and pain measures at the midpoint of the treatment period (P<.001). Patient satisfaction with care was equally high (85%) in both groups. Minimally clinically important differences in scores and number needed to treat scores (NNT<6) indicated that the experimental treatment (protocol of care) offered a clinically meaningful benefit over the control treatment (usual care), particularly at the midpoint of the treatment period. Conclusions: Overall, the 2 treatment groups were similar based on primary or secondary outcome measure scores for the full treatment period (4 weeks, with up to 7 treatments). However, there were statistically significant and clinically meaningful differences in both disability and pain scores at week 2 (midpoint) with 4 treatments, suggesting that the protocol of care had a more rapid effect than usual care. [Copyright &y& Elsevier]

Abstract: A novel series of pyridothieno-1,2,3-triazines with potent antifungal activity against Erysiphe graminis f. sp. tritici has been discovered. Two complementary synthetic routes to compounds of this type have been developed and used to efficiently explore the structure–activity relationships around the lead compound. The incorporation of oxygen atoms into the side chains of the molecules has allowed the solubility of the compounds to be increased 10-fold whilst retaining biological activity. [Copyright &y& Elsevier]

Limited research exists regarding proximity of vehicles to "vulnerable road users" and effects of "conspicuity equipment". Previous studies stated over 60% of horse/rider combinations experience near-miss traffic collisions in any one year, whereas use of fluorescent/reflective (FR) equipment did not decrease occurrences. Similarly, research into vehicle proximity to bicycles reported no significance in cyclists wearing FR. This study undertook a similar field experiment using a horse/rider combination wearing different conspicuity equipment to test proximity distance. Two horses with similar height, age, base coat color, and temperament were ridden using four conspicuity measures 60 times each (n = 240) along a straight 0.8 km lane. Measures were chosen by random crossover with two selected for each separate trip. These were an FR "tabard", a novel black/white pattern (BW), flashing lights on a helmet (L), and control of mid-blue (C). A novel proximity meter was used on the saddle pommel and distance/approach either front or rear were logged into a voice recorder. Analysis reported a significant difference between all measures and proximities observed (P =.000). Mann–Whitney tests concluded significant differences in proximity in C versus L and BW (P =.000; P =.000), respectively. FR versus C showed no significant difference in proximity (P =.005). L versus BW reported no significant difference in proximity (W = 3640.0, P =.958). Results may suggest wearing conspicuity equipment of L or BW outperforms both C and FR. Further study is recommended to test these findings, and it is pertinent to still consider suggesting the use of FR equipment due to previous positive findings with other road users. • The black and white pattern tabard and the flashing helmet lights worn separately caused a significant amount of drivers to increase their distance from the horse-rider combination. • This increase of distance, or proximity, was not seen for the combination when wearing a fluorescent/reflect tabard or a control of mid-blue color. • Therefore, results may suggest that wearing conspicuity equipment consisting of flashing lights or a black/white pattern tabard outperform both plain clothing and a fluorescent/reflective tabard in increasing the proximity distance. • As visual acuity of humans is fundamentally based on contrast, the ability of these two conspicuity factors to exploit this may provide the rider with greater space from vehicles. • However, it is pertinent to still consider suggesting the use of fluorescent/reflective equipment because of previous positive findings with other road users. [ABSTRACT FROM AUTHOR]

The genomes of all organisms are read throughout their growth and development, generating new copies during cell division and encoding the cellular activities dictated by the genome's content. However, genomes are not invariant information stores but are purposefully altered in minor and major ways, adapting cellular behaviour and driving evolution. Kinetoplastids are eukaryotic microbes that display a wide range of such read–write genome activities, in many cases affecting critical aspects of their biology, such as host adaptation. Here we discuss the range of read–write genome changes found in two well-studied kinetoplastid parasites, Trypanosoma brucei and Leishmania , focusing on recent work that suggests such adaptive genome variation is linked to novel strategies the parasites use to replicate their unconventional genomes. Polycistronic transcription dominates and shapes kinetoplastid genomes, inevitably leading to clashes with DNA replication. By harnessing the resultant DNA damage for adaptation, kinetoplastids have huge potential for dynamic read–write genome variation. Major origins of DNA replication are confined to the boundaries of polycistronic transcription units in the Trypanosoma brucei and Leishmania genomes, putatively limiting DNA damage. Subtelomeres may lack this arrangement, generating read–write hotspots. In T. brucei , early replication of the highly transcribed subtelomeric variant surface glycoprotein (VSG) expression site may ensure replication-transcription clashes within this site to trigger DNA recombination, an event critical for antigenic variation. Leishmania genomes show extensive aneuploidy and copy number variation. Notably, DNA replication requires recombination factors and relies on post-S phase replication of subtelomeres. Evolution of compartmentalised DNA replication programmes underpin important aspects of genome biology in kinetoplastids, illustrating the consolidation of genome maintenance strategies to promote genome plasticity. [ABSTRACT FROM AUTHOR]