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Human African Trypanosomiasis (HAT) has been responsible for several deadly epidemics throughout the 20th century, but a renewed commitment to disease control has significantly reduced new cases and motivated a target for the elimination of Trypanosoma brucei gambiense-HAT by 2030. However, the recent identification of latent human infections, and the detection of trypanosomes in extravascular tissues hidden from current diagnostic tools, such as the skin, has added new complexity to identifying infected individuals. New and improved diagnostic tests to detect Trypanosoma brucei infection by interrogating the skin are therefore needed. Recent advances have improved the cost, sensitivity and portability of Raman spectroscopy technology for non-invasive medical diagnostics, making it an attractive tool for gambiense-HAT detection. The aim of this work was to assess and develop a new non-invasive diagnostic method for T. brucei through Raman spectroscopy of the skin. Infections were performed in an established murine disease model using the animal-infective Trypanosoma brucei brucei subspecies. The skin of infected and matched control mice was scrutinized ex vivo using a confocal Raman microscope with 532 nm excitation and in situ at 785 nm excitation with a portable field-compatible instrument. Spectral evaluation and Principal Component Analysis confirmed discrimination of T. brucei-infected from uninfected tissue, and a characterisation of biochemical changes in lipids and proteins in parasite-infected skin indicated by prominent Raman peak intensities was performed. This study is the first to demonstrate the application of Raman spectroscopy for the detection of T. brucei by targeting the skin of the host. The technique has significant potential to discriminate between infected and non-infected tissue and could represent a unique, non-invasive diagnostic tool in the goal for elimination of gambiense-HAT as well as for Animal African Trypanosomiasis (AAT)., Competing Interests: The authors have declared that no competing interests exist.

Background: The diagnosis of gambiense human African trypanosomiasis (gHAT) typically involves 2 steps: a serological screen, followed by the detection of living trypanosome parasites in the blood or lymph node aspirate. Live parasites can, however, remain undetected in some seropositive individuals, who, we hypothesize, are infected with Trypanosoma brucei gambiense parasites in their extravascular dermis., Methods: To test this hypothesis, we conducted a prospective observational cohort study in the gHAT focus of Forecariah, Republic of Guinea. Of the 5417 subjects serologically screened for gHAT, 66 were enrolled into our study and underwent a dermatological examination. At enrollment, 11 seronegative, 8 unconfirmed seropositive, and 18 confirmed seropositive individuals had blood samples and skin biopsies taken and examined for trypanosomes by molecular and immunohistological methods., Results: In seropositive individuals, dermatological symptoms were significantly more frequent, relative to seronegative controls. T.b. gambiense parasites were present in the blood of all confirmed cases (n = 18) but not in unconfirmed seropositive individuals (n = 8). However, T. brucei parasites were detected in the extravascular dermis of all unconfirmed seropositive individuals and all confirmed cases. Skin biopsies of all treated cases and most seropositive untreated individuals progressively became negative for trypanosomes 6 and 20 months later., Conclusions: Our results highlight the skin as a potential reservoir for African trypanosomes, with implications for our understanding of this disease's epidemiology in the context of its planned elimination and underlining the skin as a novel target for gHAT diagnostics., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

The concept of self-respect has received little attention in the psychological literature and is not clearly distinguished from self-esteem. The present research sought to empirically investigate the bases of self-respect by manipulating adherence to morals together with interpersonal appraisals (IAs), or task-related competence, in hypothetical scenarios (Studies 1a and 1b) and a situation participants relived (Studies 2 and 3). Participants' levels of state self-respect and self-esteem were measured. Studies 1 to 3 found main effects of adherence to morals on self-respect, with self-respect mediating the effect of adherence to morals on self-esteem, but little support for competence and IAs directly influencing self-respect. Self-respect uniquely contributed to anticipated/felt self-esteem alongside competence or IAs. The pattern of results supports the conceptualization of self-respect as a component of self-esteem associated with morally principled conduct, distinct from performance and social self-esteem. The findings have implications for our understanding of self-esteem and moral behavior.

Background: Respectful care is central to ethical codes of practice and optimal patient care, but little is known about the influences on and challenges in communicating respect., Research Question: What are the intra- and inter-personal influences on nurses' communication of respect?, Research Design and Participants: Semi-structured interviews with 12 hospital-based UK registered nurses were analysed using interpretative phenomenological analysis to explore their experiences of communicating respect to patients and associated influences., Ethical Considerations: The study was approved by the Institutional ethics board and National Health Service Trust., Findings: Three interconnected superordinate themes were identified: 'private self: personal attitudes', 'outward self: showing respect' and 'reputational self: being perceived as respectful'. Respectful communication involved a complex set of influences, including attitudes of respect towards patients, needs and goals, beliefs around the nature of respectful communication, skills and influencing sociocultural factors. A tension between the outward self as intended and perceived presented challenges for nurses' reputational self as respectful, with negative implications for patient care., Discussion: The study offers an in-depth understanding of intra- and inter-personal influences on communicating respect, and sheds light on challenges involved, helping provide practical insights to support respectful care., Conclusion: Findings stress the need for improved conceptualisations of respect in healthcare settings to formally recognise the complex attitudinal and socially constructed nature of respect and for appropriate professional training to improve its communication.

Trypanosoma brucei (T.b.) rhodesiense is the cause of the acute form of human African trypanosomiasis (HAT) in eastern and southern African countries. There is some evidence that there is diversity in the disease progression of T.b. rhodesiense in different countries. HAT in Malawi is associated with a chronic haemo-lymphatic stage infection compared to other countries, such as Uganda, where the disease is acute with more marked neurological impairment. This has raised the question of the role of host genetic factors in infection outcomes. A candidate gene association study was conducted in the northern region of Malawi. This was a case-control study involving 202 subjects, 70 cases and 132 controls. All individuals were from one area; born in the area and had been exposed to the risk of infection since birth. Ninety-six markers were genotyped from 17 genes: IL10, IL8, IL4, HLA-G, TNFA, IL6, IFNG, MIF, APOL, HLA-A, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH. There was a strong significant association with APOL1 G2 allele (p = 0.0000105, OR = 0.14, CI95 = [0.05-0.41], BONF = 0.00068) indicating that carriers of the G2 allele were protected against T.b. rhodesiense HAT. SNP rs2069845 in IL6 had raw p < 0.05, but did not remain significant after Bonferroni correction. There were no associations found with the other 15 candidate genes. Our finding confirms results from other studies that the G2 variant of APOL1 is associated with protection against T.b. rhodesiense HAT., Competing Interests: The authors have declared that no competing interests exist.

Infection by Trypanosoma brucei gambiense is characterized by a wide array of clinical outcomes, ranging from asymptomatic to acute disease and even spontaneous cure. In this study, we investigated the association between macrophage migrating inhibitory factor (MIF), an important pro-inflammatory cytokine that plays a central role in both innate and acquired immunity, and disease outcome during T. b. gambiense infection. A comparative expression analysis of patients, individuals with latent infection and controls found that MIF had significantly higher expression in patients (n = 141; 1.25 ± 0.07; p < .0001) and latent infections (n = 25; 1.23 ± 0.13; p = .0005) relative to controls (n = 46; 0.94 ± 0.11). Furthermore, expression decreased significantly after treatment (patients before treatment n = 33; 1.40 ± 0.18 versus patients after treatment n = 33; 0.99 ± 0.10, p = .0001). We conducted a genome wide eQTL analysis on 29 controls, 128 cases and 15 latently infected individuals for whom expression and genotype data were both available. Four loci, including one containing the chemokine CXCL13, were found to associate with MIF expression. Genes at these loci are candidate regulators of increased expression of MIF after infection. Our study is the first data demonstrating that MIF expression is elevated in T. b. gambiense-infected human hosts but does not appear to contribute to pathology., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Human African trypanosomiasis (HAT), or African sleeping sickness, is a fatal disease found throughout sub-Saharan Africa. The disease is close to elimination in many areas, although it was similarly close to elimination once before and subsequently reemerged, despite seemingly low rates of transmission. Determining how these foci persisted and overcame an apparent transmission paradox is key to finally eliminating HAT. By assessing clinical, laboratory, and mathematical data, we propose that asymptomatic infections contribute to transmission through the presence of an overlooked reservoir of skin-dwelling parasites. Our assessment suggests that a combination of asymptomatic and parasitaemic cases is sufficient to maintain transmission at foci without animal reservoirs, and we argue that the current policy not to treat asymptomatic HAT should be reconsidered., Competing Interests: The authors have declared that no competing interests exist.

Respectfulness is demanded of doctors and predicts more positive patient health-related outcomes, but research is scarce on ways to promote it. This study explores two ways to conceptualize unconditional respect from medical students, defined as respect paid to people on the basis of their humanity, in order to inform strategies to increase it. Unconditional respect conceptualized as an attitude suggests that unconditional respect and conditional respect are additive, whereas unconditional respect conceptualized as a personality trait suggests that people who are high on unconditional respect afford equal respect to all humans regardless of their merits. One hundred and eighty-one medical students completed an unconditional respect measure then read a description of a respect-worthy or a non-respect-worthy man and indicated their respect towards him. The study found a main effect for unconditional respect and a main effect for target respect-worthiness but no interaction between the two when respect paid to the target was assessed, supporting the attitude-based conceptualization. This suggests that unconditional respect can be increased through relevant interventions aimed at increasing the relative salience to doctors of the human worth of individuals. Interventions to increase unconditional respect are discussed.

The role of mammalian skin in harbouring and transmitting arthropod-borne protozoan parasites has been overlooked for decades as these pathogens have been regarded primarily as blood-dwelling organisms. Intriguingly, infections with low or undetected blood parasites are common, particularly in the case of Human African Trypanosomiasis caused by Trypanosoma brucei gambiense . We hypothesise, therefore, the skin represents an anatomic reservoir of infection. Here we definitively show that substantial quantities of trypanosomes exist within the skin following experimental infection, which can be transmitted to the tsetse vector, even in the absence of detectable parasitaemia. Importantly, we demonstrate the presence of extravascular parasites in human skin biopsies from undiagnosed individuals. The identification of this novel reservoir requires a re-evaluation of current diagnostic methods and control policies. More broadly, our results indicate that transmission is a key evolutionary force driving parasite extravasation that could further result in tissue invasion-dependent pathology., Competing Interests: The authors declare that no competing interests exist.

Humans are protected against infection from most African trypanosomes by lipoprotein complexes present in serum that contain the trypanolytic pore-forming protein, Apolipoprotein L1 (APOL1). The human-infective trypanosomes, Trypanosoma brucei rhodesiense in East Africa and T. b. gambiense in West Africa have separately evolved mechanisms that allow them to resist APOL1-mediated lysis and cause human African trypanosomiasis, or sleeping sickness, in man. Recently, APOL1 variants were identified from a subset of Old World monkeys, that are able to lyse East African T. b. rhodesiense, by virtue of C-terminal polymorphisms in the APOL1 protein that hinder that parasite's resistance mechanism. Such variants have been proposed as candidates for developing therapeutic alternatives to the unsatisfactory anti-trypanosomal drugs currently in use. Here we demonstrate the in vitro lytic ability of serum and purified recombinant protein of an APOL1 ortholog from the West African Guinea baboon (Papio papio), which is able to lyse examples of all sub-species of T. brucei including T. b. gambiense group 1 parasites, the most common agent of human African trypanosomiasis. The identification of a variant of APOL1 with trypanolytic ability for both human-infective T. brucei sub-species could be a candidate for universal APOL1-based therapeutic strategies, targeted against all pathogenic African trypanosomes.

Purpose: Respect experiences are poorly understood despite respect being central to professionalism in health care and patient well-being, and needed for optimal patient care. This study explores which patient-perceived communication behaviours from hospital staff contribute most to cancer patients' respect experiences and account for variation in their experience by socio-demographic and clinical characteristics., Methods: We present a secondary analysis of data from the 2012-2013 National Cancer Patient Experience Survey of 45,191 patients with a primary cancer diagnosis treated in English National Health Service trusts providing adult acute cancer services who provided data on experienced respect and dignity., Results: Both autonomy-supportive and caring/emotionally sensitive behaviours were associated with reported respect, although the latter showed stronger associations and accounted for most differences in reports of respect between patient groups. Differences in respect were found by gender, race/ethnicity, age, the presence of long-standing conditions, treatment response, time since first treated for cancer (p < .001), employment and type of cancer (p < .05)., Conclusions: The study questions the tendency to conceptualise respect primarily in terms of autonomy-supportive behaviours and shows the relative contribution of autonomy-supportive and caring/emotionally sensitive behaviours in explaining disparities in respect experiences. More attention should be paid to affective communication behaviours from hospital staff to reduce disparities in respect experiences.

Evolutionary theory predicts that the lack of recombination and chromosomal re-assortment in strictly asexual organisms results in homologous chromosomes irreversibly accumulating mutations and thus evolving independently of each other, a phenomenon termed the Meselson effect. We apply a population genomics approach to examine this effect in an important human pathogen, Trypanosoma brucei gambiense. We determine that T.b. gambiense is evolving strictly asexually and is derived from a single progenitor, which emerged within the last 10,000 years. We demonstrate the Meselson effect for the first time at the genome-wide level in any organism and show large regions of loss of heterozygosity, which we hypothesise to be a short-term compensatory mechanism for counteracting deleterious mutations. Our study sheds new light on the genomic and evolutionary consequences of strict asexuality, which this pathogen uses as it exploits a new biological niche, the human population.

Trypanosoma brucei is the causative agent of African sleeping sickness in humans and one of several pathogens that cause the related veterinary disease Nagana. A complex co-evolution has occurred between these parasites and primates that led to the emergence of trypanosome-specific defences and counter-measures. The first line of defence in humans and several other catarrhine primates is the trypanolytic protein apolipoprotein-L1 (APOL1) found within two serum protein complexes, trypanosome lytic factor 1 and 2 (TLF-1 and TLF-2). Two sub-species of T. brucei have evolved specific mechanisms to overcome this innate resistance, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. In T. b. rhodesiense, the presence of the serum resistance associated (SRA) gene, a truncated variable surface glycoprotein (VSG), is sufficient to confer resistance to lysis. The resistance mechanism of T. b. gambiense is more complex, involving multiple components: reduction in binding affinity of a receptor for TLF, increased cysteine protease activity and the presence of the truncated VSG, T. b. gambiense-specific glycoprotein (TgsGP). In a striking example of co-evolution, evidence is emerging that primates are responding to challenge by T. b. gambiense and T. b. rhodesiense, with several populations of humans and primates displaying resistance to infection by these two sub-species.

Short-term effectiveness of the International Child Development Programme (ICDP) for parents in the general population has been studied. The aim of this paper was to investigate the longer term impact of the ICDP programme on parents looking for sustained changes 6-12 months after the programme. For this, a non-clinical caregiver group attending the ICDP programme ( N  = 79) and a non-attending comparison group ( N  = 62) completed questionnaires on parenting, psychosocial functioning, and child difficulties before, on completion and 6-12 months after the ICDP programme. Analyses compare changes in scores over time. The results revealed that the ICDP group showed significantly improved scores on parenting measures, less loneliness, and trends towards improved self-efficacy compared to the comparison group 6-12 months after programme completion. The ICDP group also reported that their children spent significantly less time on television and computer games and a trend towards fewer child difficulties. Key positive effects sustained over time but at a somewhat lower level, supporting community-wide implementation of ICDP as a general parenting programme. It is concluded that more intensive training with follow-up sessions should be considered to sustain and boost initial gains.

Elucidating the underlying genetic determinants of disease pathology is still in the early stages for many pathogenic parasites. There have, however, been a number of advances in which natural genetic diversity has been successfully utilized to untangle the often complex interactions between parasite and host. In this chapter we discuss various methods capable of exploiting this natural genetic variation to determine genes involved in phenotypes of interest, using virulence in the pathogenic parasite Trypanosoma brucei as a case study. This species is an ideal system to benefit from such an approach as there are several well-characterized laboratory strains; the parasite undergoes genetic exchange in both the field and the laboratory, and is amenable to efficient reverse genetics and RNAi.

Aim: To explore student nurses' understanding and behaviours of respect towards patients in order to inform educational strategies to optimise respectful care., Background: There is a causal relationship between the perception of being treated with respect and patient satisfaction. Concerns over standards of care prompted a commissioned report into the quality of nurse education in the United Kingdom., Design: A hermeneutic phenomenological interview study was used to identify and interpret student nurses' behaviours and understanding of respect towards patients., Setting: University health and social care faculty in the north-west of England, United Kingdom., Participants: Eight third-year student nurses (adult branch), on different university sites, with practice placements across different healthcare trusts., Methods: Interviews about their understanding of respect and their behavioural intentions of respect towards patients were recorded and transcribed, then analysed using interpretative phenomenological analysis (IPA) to produce themes from the data., Findings: Three themes of relevance to nurse education were identified. Respect is a complex concept that is difficult to apply in practice. Students are not always aware of incongruence between their feelings of respect towards patients and their behaviours towards them. Role-modelling of respectful care is variable, and essential care is often learned from healthcare assistants., Discussion: Awareness of emotional responses and their relationship to patient perceptions of respect should be facilitated in theory and practice. Rehearsal of the application of respect involving emotional labour, and reflection in and on the practice of respectful care, are needed to address student learning needs. The theory-practice gap in relation to respect, variation in professional practice and the under-recognised importance of healthcare assistants in student nurse education, are barriers to the learning of respect to patients., Conclusions: Interactive education experiences are important to develop self-awareness and insight into respectful care. Mentorship in practice should encourage reflection in and on the practice of respect towards patients., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: Trypanosoma brucei drug transporters include the TbAT1/P2 aminopurine transporter and the high-affinity pentamidine transporter (HAPT1), but the genetic identity of HAPT1 is unknown. We recently reported that loss of T. brucei aquaglyceroporin 2 (TbAQP2) caused melarsoprol/pentamidine cross-resistance (MPXR) in these parasites and the current study aims to delineate the mechanism by which this occurs., Methods: The TbAQP2 loci of isogenic pairs of drug-susceptible and MPXR strains of T. brucei subspecies were sequenced. Drug susceptibility profiles of trypanosome strains were correlated with expression of mutated TbAQP2 alleles. Pentamidine transport was studied in T. brucei subspecies expressing TbAQP2 variants., Results: All MPXR strains examined contained TbAQP2 deletions or rearrangements, regardless of whether the strains were originally adapted in vitro or in vivo to arsenicals or to pentamidine. The MPXR strains and AQP2 knockout strains had lost HAPT1 activity. Reintroduction of TbAQP2 in MPXR trypanosomes restored susceptibility to the drugs and reinstated HAPT1 activity, but did not change the activity of TbAT1/P2. Expression of TbAQP2 sensitized Leishmania mexicana promastigotes 40-fold to pentamidine and >1000-fold to melaminophenyl arsenicals and induced a high-affinity pentamidine transport activity indistinguishable from HAPT1 by Km and inhibitor profile. Grafting the TbAQP2 selectivity filter amino acid residues onto a chimeric allele of AQP2 and AQP3 partly restored susceptibility to pentamidine and an arsenical., Conclusions: TbAQP2 mediates high-affinity uptake of pentamidine and melaminophenyl arsenicals in trypanosomes and TbAQP2 encodes the previously reported HAPT1 activity. This finding establishes TbAQP2 as an important drug transporter.

Background: Many parenting programmes lack proper evaluation, especially under community-wide implementation., Objective: Examining the effectiveness of the eight-week International Child Development Programme (ICDP), implemented as a general programme., Methodology: Non-clinical caregivers attending ICDP ( N = 141) and a non-attending community comparison group ( N = 79) completed questionnaires on parenting, psychosocial functioning, and child difficulties before and after ICDP course. Analyses compare changes in scores for both groups over time., Results: The ICDP group showed more positive attitudes towards child management and reported better child management, improved parental strategies and less impact of child difficulties. Caregivers with low initial scores benefited most. The comparison group showed little change with a significant decrease in scores on the caregiver-child activity scale., Discussion: The results suggest that caregivers in the community who do not show clinical signs or have children with behaviour or other disorders, may benefit from participating in parent training based on ICDP.

There is a high level of orphaning in Africa due to war, violence, and more recently HIV and AIDS. This study examines parental death in South African children and examines the differential impact on child functioning of double, single and non-orphanhoods. Bereavement, depression, behavior problems, and violence were examined in a consecutive sample of 381 children/adolescents (51.2% girls) between 8 and 19 years of age (M = 12.8). Parental death experience was high; 70 (17.5%) reported the death of one parent, and a further 24 (6%) reported the death of both. Group comparisons showed double orphans had elevated depression, worse psychosocial functioning, were more likely to be kept home from school for household chores, and were more likely to be slapped. Single orphans were more similar to the non-orphans than the double orphans on most scores. Our study reveals that parental loss should be studied with more fine-grained definitions and that emotional sequelae should be addressed.

Very little is known regarding health-care professionals' understanding and experiences of respect towards patients. The study aimed to explore student nurses' understanding and experiences of respect in their encounters with patients. Semi-structured interviews were conducted with eight final-year student nurses with practice placements across different health-care trusts in the UK. Transcripts were analysed using interpretative phenomenological analysis (IPA). Three super-ordinate themes were identified: understanding of what it means to show respect, negotiating role expectations and personal attitudes in practice, and barriers related to the performance of the nursing role. The factors identified should be investigated further and addressed as they are likely to influence patients' experiences of feeling respected in nurse-patient interactions and subsequently their well-being and health-related behaviours.

Trypanosoma brucei gambiense causes 97% of all cases of African sleeping sickness, a fatal disease of sub-Saharan Africa. Most species of trypanosome, such as T. b. brucei, are unable to infect humans due to the trypanolytic serum protein apolipoprotein-L1 (APOL1) delivered via two trypanosome lytic factors (TLF-1 and TLF-2). Understanding how T. b. gambiense overcomes these factors and infects humans is of major importance in the fight against this disease. Previous work indicated that a failure to take up TLF-1 in T. b. gambiense contributes to resistance to TLF-1, although another mechanism is required to overcome TLF-2. Here, we have examined a T. b. gambiense specific gene, TgsGP, which had previously been suggested, but not shown, to be involved in serum resistance. We show that TgsGP is essential for resistance to lysis as deletion of TgsGP in T. b. gambiense renders the parasites sensitive to human serum and recombinant APOL1. Deletion of TgsGP in T. b. gambiense modified to uptake TLF-1 showed sensitivity to TLF-1, APOL1 and human serum. Reintroducing TgsGP into knockout parasite lines restored resistance. We conclude that TgsGP is essential for human serum resistance in T. b. gambiense.

Objective: To investigate, in line with the "hearing-aid effect", whether medical students would have less respect for a young male with a hearing aid than without when he was described as either respectworthy (i.e. as deserving respect) or non-respectworthy, and whether their attitudes differed from non-medical students. The interaction between the presence/absence of a hearing aid and respectworthiness on respect level was also explored., Design: Participants were shown a photograph and a written description of a young male. They were pseudo-randomly assigned to one of four core conditions reflecting the presence or absence of a hearing aid and the young man's respectworthiness, and completed questions regarding their behaviours, beliefs, and feelings of respect towards him., Study Sample: One hundred and eighty-one medical students and a control group of 92 non-medical students., Results: Results showed more respect for the young male with a hearing aid than without from female participants, and for the young male described as respectworthy compared to non-respectworthy in medical and in non-medical students. However, medical students had more respect for the young male with and without a hearing aid than non-medical students., Conclusions: Findings were contrary to the "hearing-aid effect". Possible explanations are given and implications are discussed.

This study aimed to determine demographic, behavioural and self-report disease/treatment variables among HIV-infected individuals (n = 666) that predict unprotected intercourse with a partner of unknown/discordant status. Sexual risk behaviour was reported by 12.8%. In multivariable analysis, risk was more likely to be reported by gay men compared to women or heterosexual men, and for those with higher psychological symptom burden. Psychological symptoms should be assessed and managed in the HIV outpatient setting to ensure integrated care that enhances prevention.

Patient self-reported outcomes are increasingly important in measuring disease, treatment and care outcomes. It is unclear what constitutes well-being using a combined biomedical and psychosocial approach for patients with antiretroviral therapy (ART) access. This study aimed to determine the variance within the visual analogue scale (VAS) measure of health status using the existing five dimensions of the EuroQOL-5D, to identify which domains have the greatest effect on self-reported health status and to identify associations with the VAS using both biomedical and psychosocial factors among HIV outpatients. Consecutive patients in five UK clinics were recruited to a cross-sectional survey, n=778 (86% response rate). Patients self-completed validated measures, with treatment variables extracted from file. On the EuroQOL-5D, nearly one-third (28.1%) had mobility problems, one-fifth (18.7%) self-care problems, one-third (37.4%) difficulty in performing usual tasks and one-half (44.4%) reported pain/discomfort. In the regression model to determine associations with self-reported health status (VAS score), neither CD4 count nor ART status was associated with the outcome. However, in addition to four dimensions of the EuroQOL-5D, poorer health status was associated with worse physical symptom burden, treatment optimism and psychological symptoms. There is a relatively high prevalence of psychological morbidity and poor physical function, and these burdens of disease are associated with worse self-reported health status. As HIV management focuses on treatment for extended survival and a chronic model of disease, clinical attention to physical and psychological dimensions of patient care are essential to achieve optimal well-being.

Microtubule severing enzymes regulate microtubule dynamics in a wide range of organisms and are implicated in important cell cycle processes such as mitotic spindle assembly and disassembly, chromosome movement and cytokinesis. Here we explore the function of several microtubule severing enzyme homologues, the katanins (KAT80, KAT60a, KAT60b and KAT60c), spastin (SPA) and fidgetin (FID) in the bloodstream stage of the African trypanosome parasite, Trypanosoma brucei. The trypanosome cytoskeleton is microtubule based and remains assembled throughout the cell cycle, necessitating its remodelling during cytokinesis. Using RNA interference to deplete individual proteins, we show that the trypanosome katanin and spastin homologues are non-redundant and essential for bloodstream form proliferation. Further, cell cycle analysis revealed that these proteins play essential but discrete roles in cytokinesis. The KAT60 proteins each appear to be important during the early stages of cytokinesis, while downregulation of KAT80 specifically inhibited furrow ingression and SPA depletion prevented completion of abscission. In contrast, RNA interference of FID did not result in any discernible effects. We propose that the stable microtubule cytoskeleton of T. brucei necessitates the coordinated action of a family of katanins and spastin to bring about the cytoskeletal remodelling necessary to complete cell division.

Gender is important in the experience of illness generally and HIV specifically. In this study the authors compare 183 HIV positive women with 76 HIV positive heterosexual men attending United Kingdom HIV clinics on clinical, treatment, and mental health factors. Participants completed a questionnaire on mental health and HIV-related factors. Laboratory measures of HIV viral load and CD4 cell count were obtained at baseline and 6-18 months later. After adjusting for age, employment, and treatment status, men were significantly less likely than women to suffer from high psychological [adjusted odds ratio (OR) = 0.38, 95% confidence interval (CI): 0.17, 0.86] and global symptom distress (adjusted OR = 0.42, 95% CI: 0.19, 0.92). However, men were more likely than women to report having suicidal thoughts (adjusted OR = 1.85, 95% CI: 0.95, 3.58). Relational, sexual behavior, and quality of life factors were similar for men and women. Adherence levels did not differ by gender but were sub-optimal in 56% of patients. Men had significantly lower CD4 counts than women at baseline, but not at follow-up. No differences were observed in the proportions with viral suppression. The groups had generally similar HIV experiences with high psychological distress. Adherence monitoring and gender appropriate psychological support are needed for these groups.

People with human immunodeficiency virus (HIV) show elevated anxiety levels compared to the general population. Anxiety can predate HIV infection or be triggered by HIV diagnosis and the many stresses that emerge during the course of HIV disease. Many psychological and pharmacological therapies have been shown to treat anxiety in the general population but a systematic understanding of which interventions have been tested in and are effective with HIV-seropositive individuals is needed. This review examines all published intervention studies on anxiety and HIV from 1980 to 2009 covered by the databases MedLine (1980-2009) and PsycINFO (1980-2009) for a definitive account of effectiveness of interventions and an indication of prevalence of HIV-related anxiety and measurement within studies. Standard systematic research methods were used to gather quality published papers on HIV and anxiety, searching published data bases according to quality inclusion criteria. From the search, 492 papers were generated and hand searched resulting in 39 studies meeting adequacy inclusion criteria for analysis. Of these, 30 (76.9%) were implemented in North America (the USA and Canada), with little representation from developing countries. Thirty-three (84.6%) studies recruited only men or mostly men. A total of 50 interventions were investigated by the 39 studies; 13 targeted HIV, symptoms or associated outcomes/conditions, 20 directly targeted anxiety and another 17 indirectly targeted anxiety. Twenty-four (48%) interventions were effective in reducing anxiety (including 11 indirect interventions), 16 (32%) were ineffective and 10 (20%) had an unknown effect on anxiety. Sixty-five percent of interventions directly targeting anxiety were effective. Psychological interventions (especially cognitive behavioural stress management interventions and cognitive behavioural therapy) were generally more effective than pharmacological interventions. Only three studies provided prevalence rates - these ranged from 13% to 80%. Anxiety was measured using 16 different instruments. Our detailed data suggest that interventions are both effective and available, although further research into enhancing efficacy would be valuable. Also, the vast majority of studies were Western-based, no studies looked at children or adolescents and few looked specifically at women. An international effort to harmonise measurement of anxiety is also missing. There is a need to routinely log anxiety in those with HIV infection during the course of their disease, to provide specific data on women, young people and those in diverse geographic areas and incorporate management into care protocols.

Suicide has long been associated with serious illness generally and HIV specifically. New treatments have affected prognosis in HIV positively, but it is unclear how they impact on suicidal burden (thoughts, self-harm and completions). This review examines all published suicide and HIV data for a definitive account of (1) prevalence of HIV-related suicidality, (2) measurement within studies and (3) effectiveness of interventions. Standard systematic research methods were used to gather quality published papers on HIV and suicide, searching published databases according to quality inclusion criteria. From the search, 332 papers were generated and hand searched resulting in 66 studies for analysis. Of these, 75% were American/European, but there was representation from developing countries. The breakdown of papers provided 12, which measured completed suicides (death records), five reporting suicide as a cause of attrition. Deliberate self-harm was measured in 21, using 22 instruments; 16 studies measured suicidal ideation using 14 instruments, suicidal thoughts were measured in 17, using 15 instruments. Navigating the diverse range of studies clearly points to a high-suicidal burden among people with HIV. The overview shows that autopsy studies reveal 9.4% of deceased HIV+ individuals had committed suicide; 2.4% HIV+ study participants commit suicide; approximately 20% of HIV+ people studied had deliberately harmed themselves; 26.9% reported suicidal ideation, 28.5% during the past week and 6.5% reported ideation as a side effect to medication; 22.2% had a suicide plan; 19.7% were generally "suicidal" (11.7% of people with AIDS, 15.3% at other stages of HIV); 23.1% reported thoughts of ending their own life; and 14.4% expressed a desire for death. Only three studies recruited over 70% female participants (39 studies recruited over 70% men), and six focussed on injecting drug users. Only three studies looked at interventions - predominantly indirect. Our detailed data suggest that all aspects of suicide are elevated and urgently require routine monitoring and tracking as a standard component of clinical care. There is scant evidence of direct interventions to reduce any aspect of suicidality, which needs urgent redress.

HIV-positive individuals are more likely to be diagnosed with major depressive disorder than HIV-negative individuals. Depression can precede diagnosis and be associated with risk factors for infection. The experience of illness can also exacerbate depressive episodes and depression can be a side effect to treatment. A systematic understanding of which interventions have been tested in and are effective with HIV-seropositive individuals is needed. This review aims to provide a comprehensive understanding of evaluated interventions related to HIV and depression and provide some insight on questions of prevalence and measurement. Standard systematic research methods were used to gather quality published papers on HIV and depression. From the search, 1015 articles were generated and hand searched resulting in 90 studies meeting adequacy inclusion criteria for analysis. Of these, 67 (74.4%) were implemented in North America (the US and Canada) and 14 (15.5%) in Europe, with little representation from Africa, Asia and South America. Sixty-five (65.5%) studies recruited only men or mostly men, of which 31 (35%) recruited gay or bisexual men. Prevalence rates of depression ranged from 0 to 80%; measures were diverse and rarely adopted the same cut-off points. Twenty-one standardized instruments were used to measure depression. Ninety-nine interventions were investigated. The interventions were diverse and could broadly be categorized into psychological, psychotropic, psychosocial, physical, HIV-specific health psychology interventions and HIV treatment-related interventions. Psychological interventions were particularly effective and in particular interventions that incorporated a cognitive-behavioural component. Psychotropic and HIV-specific health psychology interventions were generally effective. Evidence is not clear-cut regarding the effectiveness of physical therapies and psychosocial interventions were generally ineffective. Interventions that investigated the effects of treatments for HIV and HIV-associated conditions on depression generally found that these treatments did not increase but often decreased depression. Interventions are both effective and available, although further research into enhancing efficacy would be valuable. Depression needs to be routinely logged in those with HIV infection during the course of their disease. Specific data on women, young people, heterosexual men, drug users and those indiverse geographic areas are needed. Measurement of depression needs to be harmonized and management into care protocols incorporated.

The phenomenon of post-traumatic stress has been well documented in the literature as a lasting mental health condition associated with exposure to traumatic life events. The diagnosis and experience of human immunodeficiency virus (HIV) disease may be such a trauma. On the other hand, the phenomenon of post-traumatic growth (PTG) has been described, whereby people show positive mental health growth in the face of such trauma. This systematic review was set out to explore post-traumatic stress disorder (PTSD) and PTG in people with HIV to monitor prevalence, measurement and efficacy of interventions to reduce stress and/or promote growth. Standardised review techniques were used to track reports on both PTSD and PTG. A total of 206 papers were retrieved from the PTSD and HIV searches, and 13 from the PTG and HIV searches. After reviewing the papers for inclusion according to adequacy and relevance criteria and to remove duplicates, 33 PTSD papers and three PTG were available for full coding. Prevalence of PTSD in HIV ranged from 5% to 74%, which were much greater than the 7-10% in the general population. Seven studies showed a relation between trauma and PTSD, while six showed a link between PTSD diagnosis and reduced antiretroviral treatment adherence. Women were more likely to be diagnosed with PTSD. Only three intervention reports were identified that fitted our inclusion criteria. All of these reported on psychological interventions for HIV+ individuals with trauma. The interventions utilised HIV education, training in coping techniques and support groups. Only coping interventions were shown to be effective. PTG was under researched but showed a promising avenue of study. There needs to be harmonised measurement and the evidence base would need strengthening in order to build on the understanding of the impact of PTSD and PTG over the course of HIV disease. There is good evidence to associate HIV diagnosis and experiences during the course of illness as traumatic. PTSD has been shown to be prevalent and there seems to be good evidence to incorporate standardised measures to track the course of the disorder. There is extremely limited evidence that interventions may affect the course of symptom experience. The evidence and insight into PTG show promise but is currently inadequate.

The study aimed to investigate the effect of patients' self-respect on their experience of feeling respected in doctor-patient interactions. It also explored influences of different behaviours of doctors on patients' experience of feeling respected. Forty-five participants were invited to identify with either a respect worthy or non-respect worthy self-description in random order and subsequently, to watch a series of ten video clips of doctor-patient interactions, while imagining they were the patients depicted. The video clips were designed to illustrate five behaviours of doctors that varied in terms of respectfulness. After watching each one, participants indicated how respected they felt on a visual analogue scale. Results showed a significant main effect of self-description on participants' feelings of being respected. Differences between the effects of doctors' behaviours on participants' feelings of being respected were also observed. The study thus showed that patients' self-respect is likely to have an impact on how respected they feel when interacting with their doctor. Implications of this for the quality of the doctor-patient relationship and patient health outcomes are raised. Implications of the respect shown by doctors are also discussed.

Coordination between cell fate specification and cell cycle control in multicellular organisms is essential to regulate cell numbers in tissues and organs during development, and its failure may lead to oncogenesis. In mammalian cells, as part of a general cell cycle checkpoint mechanism, the F-box protein beta-transducin repeat-containing protein (beta-TrCP) and the Skp1/Cul1/F-box complex control the periodic cell cycle fluctuations in abundance of the CDC25A and B phosphatases. Here, we find that the Caenorhabditis elegans beta-TrCP orthologue LIN-23 regulates a progressive decline of CDC-25.1 abundance over several embryonic cell cycles and specifies cell number of one tissue, the embryonic intestine. The negative regulation of CDC-25.1 abundance by LIN-23 may be developmentally controlled because CDC-25.1 accumulates over time within the developing germline, where LIN-23 is also present. Concurrent with the destabilization of CDC-25.1, LIN-23 displays a spatially dynamic behavior in the embryo, periodically entering a nuclear compartment where CDC-25.1 is abundant.

The P2 aminopurine transporter, encoded by TbAT1 in African trypanosomes in the Trypanosoma brucei group, carries melaminophenyl arsenical and diamidine drugs into these parasites. Loss of this transporter contributes to drug resistance. We identified the genomic location of TbAT1 to be in the subtelomeric region of chromosome 5 and determined the status of the TbAT1 gene in two trypanosome lines selected for resistance to the melaminophenyl arsenical, melarsamine hydrochloride (Cymelarsan), and in a Trypanosoma equiperdum clone selected for resistance to the diamidine, diminazene aceturate. In the Trypanosoma brucei gambiense STIB 386 melarsamine hydrochloride-resistant line, TbAT1 is deleted, while in the Trypanosoma brucei brucei STIB 247 melarsamine hydrochloride-resistant and T. equiperdum diminazene-resistant lines, TbAT1 is present, but expression at the RNA level is no longer detectable. Further characterization of TbAT1 in T. equiperdum revealed that a loss of heterozygosity at the TbAT1 locus accompanied loss of expression and that P2-mediated uptake of [(3)H]diminazene is lost in drug-resistant T. equiperdum. Adenine-inhibitable adenosine uptake is still detectable in a DeltaTbat1 T. b. brucei mutant, although at a greatly reduced capacity compared to that of the wild type, indicating that an additional adenine-inhibitable adenosine permease, distinct from P2, is present in these cells.

Background: The protozoan parasite, Trypanosoma brucei, is spread by the tsetse fly and causes Human African Trypanosomiasis. Its cell cycle is complex and not fully understood at the molecular level. The T. brucei genome contains over 6000 protein coding genes with >50% having no predicted function. A small scale RNA interference (RNAi) screen was carried out in Trypanosoma brucei to evaluate the prospects for identifying novel cycle regulators., Results: Procyclic form T. brucei were transfected with a genomic RNAi library and 204 clones isolated. However, only 76 RNAi clones were found to target a protein coding gene of potential interest. These clones were screened for defects in proliferation and cell cycle progression following RNAi induction. Sixteen clones exhibited proliferation defects upon RNAi induction, with eight clones displaying potential cell cycle defects. To confirm the phenotypes, new RNAi cell lines were generated and characterised for five genes targeted in these clones. While we confirmed that the targeted genes are essential for proliferation, we were unable to unambiguously classify them as cell cycle regulators., Conclusion: Our study identified genes essential for proliferation, but did not, as hoped, identify novel cell cycle regulators. Screening of the RNAi library for essential genes was extremely labour-intensive, which was compounded by the suboptimal quality of the library. For such a screening method to be viable for a large scale or genome wide screen, a new, significantly improved RNAi library will be required, and automated phenotyping approaches will need to be incorporated.

SEC-23 is a component of coat protein complex II (COPII)-coated vesicles involved in the endoplasmic reticulum-to-Golgi transport pathway of eukaryotes. During postembryonic life, Caenorhabditis elegans is surrounded by a collagenous exoskeleton termed the cuticle. From a screen for mutants defective in cuticle secretion, we identified and characterized a sec-23 mutant of C. elegans. By sequence homology, C. elegans has only the single sec-23 gene described herein. In addition to the cuticle secretion defect, mutants fail to complete embryonic morphogenesis. However, they progress through the earlier stages of embryogenesis, including gastrulation, and achieve substantial morphogenesis before death. We demonstrated a maternal component of SEC-23 function sufficient for progression through the earlier stages of embryogenesis and explaining the limited phenotype of the zygotic mutant. By RNA-mediated interference, we investigated the effects of perturbing COPII function during various postembryonic stages. During larval stages, major defects in cuticle synthesis and molting were observed. In the adult hermaphrodite, reduction of SEC-23 function by RNA-mediated interference caused a rapid onset of sterility, with defects in oogenesis including early maturation of the germline nuclei, probably a result of the observed loss of the GLP-1 receptor from the membrane surfaces adjacent to the developing germline nuclei.

In multicellular organisms, developmental programmes must integrate with central cell cycle regulation to co-ordinate developmental decisions with cell proliferation. Hyperplasia caused by deregulated proliferation without significant change to other aspects of developmental behaviour is a probable step towards full oncogenesis in many malignancies. CDC25 phosphatase promotes progression through the eukaryotic cell cycle by dephosphorylation of cyclin-dependent kinase and, in humans, different cdc25 family members have been implicated as potential oncogenes. Demonstrating the direct oncogenic potential of a cdc25 gene, we identify a gain-of-function mutant allele of the Caenorhabditis elegans gene cdc-25.1 that causes a deregulated proliferation of intestinal cells resulting in hyperplasia, while other aspects of intestinal cell function are retained. Using RNA-mediated interference, we demonstrate modulation of the oncogenic behaviour of this mutant, and show that a reduction of the wild-type cdc-25.1 activity can cause a failure of proliferation of intestinal and other cell types. That gain and loss of CDC-25.1 activity has opposite effects on cellular proliferation indicates its critical role in controlling C.elegans cell number.