The effects of needle-sharing and opioid substitution therapy on incidence of hepatitis C virus infection and reinfection in people who inject drugs.

Although high hepatitis C virus (HCV) prevalence has been observed in people who inject drugs (PWID) for decades, research suggests incidence is falling. We examined whether PWIDs' use of opioid substitution therapy (OST) and their needle-and-syringe sharing behaviour explained HCV incidence. We assessed HCV incidence in 235 PWID in Melbourne, Australia, and performed discrete-time survival with needle-sharing and OST status as independent variables. HCV infection, reinfection and combined infection/reinfection incidences were 7·6 [95% confidence interval (CI) 4·8-11·9], 12·4 (95% CI 9·1-17·0) and 9·7 (95% CI 7·4-12·6) per 100 person-years, respectively. Needle-sharing was significantly associated with higher incidence of naive HCV infection [hazard ratio (HR) 4·9, 95% CI 1·3-17·7] but not reinfection (HR 1·85, 95% CI 0·79-4·32); however, a cross-model test suggested this difference was sample specific. Past month use of OST had non-significant protective effects against naive HCV infection and reinfection. Our data confirm previous evidence of greatly reduced HCV incidence in PWID, but not the significant protective effect of OST on HCV incidence detected in recent studies. Our findings reinforce the need for greater access to HCV testing and prevention services to accelerate the decline in incidence, and HCV treatment, management and support to limit reinfection.

A decade of research using the CASP scale: key findings and future directions.

Since the publication of A Measure of Quality of Life in Early Old Age: The Theory, Development and Properties of a Needs Satisfaction Model (CASP-19) just over 10 years ago, the scale has gone on to be used in a wide variety of studies in over 20 countries across the world and the original paper has become the most highly cited paper for Aging and Mental Health. Therefore it was felt that it was a good time to look back and reflect on the developments in the use of the scale as well as to look forward to what new research is being done and could be done with the measure. To this end we are extremely grateful for the editors for allowing us to bring together a collection of papers that represent cutting edge research using the CASP scale. These papers cover a wide variety of issues, from working conditions to religiosity, from a range of countries, covering Western and Eastern Europe as well as Africa. Each makes an important individual contribution to our understanding of the factors that influence quality of life in later life as well as pointing to the limitations of the measure and future work that can be done in this area.

Trust and service engagement among people who inject drugs after release from prison.

BACKGROUND: Compounding histories of injecting drug use and incarceration can marginalise people engaging with services, making it difficult for them to address their health and social welfare needs, particularly when they navigate community re-entry service supports. Drawing on Hall and colleagues' five components of trust, this paper seeks to understand how trust in service providers fosters (or inhibits) effective service engagement from the perspective of people who inject drugs during the prison post-release period. METHODS: Between September 2018 and May 2020, qualitative in-depth interviews were completed with 48 adults (33 men, 15 women) recruited from SuperMIX (a longitudinal cohort study of people with a history of injection drug use in Victoria, Australia). Data relating to service engagement were coded against the five components of trust: competence, fidelity, honesty, global trust, and confidence. RESULTS: Reflections of post-release service engagement frequently focused on interactions with community corrections (parole) officers. Depictions of trust were consistently portrayed within the context of negative experiences and deficits, whereby trusting provider relationships and interactions were rarely described. Most participants recounted a stark absence of fidelity (that is, "pursuing a [client's] best interests"), with some participants detailing circumstances in which their vulnerability was purposefully, almost strategically, exploited. These encounters nearly always had the consequence of impeding the participant's positive progression in the post-release integration period. CONCLUSION: There is an urgent need to prioritise the client in health and social service delivery in the post-release transition-to-community period and recognise the importance of trust in delivering effective services to people whose life histories make them highly vulnerable to marginalisation.

The APPLE Tree programme: Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce-randomised controlled trial.

BACKGROUND: Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years. METHODS: A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. DISCUSSION: If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns. TRIAL REGISTRATION: ISRCTN17325135 . Registration date 27 November 2019.

A comparison of two intravesical bladder instillations for interstitial cystitis/bladder pain syndrome.

OBJECTIVE: Bladder pain syndrome (BPS) is a chronic pain condition associated with injury to the glycosoaminoglycan (GAG) layer. We aimed to prospectively evaluate iAluRil® with multi-centre tertiary urogynaecology collaboration. We hypothesised that iAluRil® (a GAG therapy) would demonstrate equivalent symptom, pain and QOL scores compared to DMSO controls. STUDY DESIGN: iAluRil® was administered for 7 instillations over 3 months in 34 women over 6 sites. 18 historical DMSO controls were matched 2:1. At baseline and 3 months post treatment validated questionnaires were collected. RESULTS: Both iAluRil® and DMSO were associated with statistically significant improvements in IC/BPS specific questionnaire scores. iAluRil® showed statistically significant improvements in pain, symptoms, and QOL. 45 % of iAluRil® recipients had a greater than 50 % reduction in pain score as represented by the VAS. DMSO was also effective in improving measures of IC/BPS with statistically significant decreases in ICSI and ICPI. There was no statistically significant difference in the size of the effect between DMSO and IAluRil®. CONCLUSIONS: iAluRil® is well tolerated and associated with significant improvements in pain and symptom scores. Almost half of refractory BPS will have a 50 % decrease in pain score at three months post treatment. This effect size is similar to DMSO.

Aging without agency: theorizing the fourth age.

This article looks at the "fourth age" as a manifestation of the fragmentation of "old age". We argue that the fourth age emerges from the institutionalization of the infirmities of old age set against the appearance of a third-age culture that negates past representations of old age. We outline the historical marginalization of old age from early modern society to the contemporary concentration of infirmity within long-term care which makes of old age an undesirable "social imaginary". As "old age" fades from the social world, we liken this to the impact of a "black hole" distorting the gravitational field surrounding it, unobservable except for its traces. Within this perspective, the fourth age can be understood by examining not the experience itself but its impact on the discourses that surround and orientate themselves to it.

Vaginal repair with mesh versus colporrhaphy for prolapse: a randomised controlled trial.

OBJECTIVE: To compare vaginal repair augmented by mesh with traditional colporrhaphy for the treatment of pelvic organ prolapse. DESIGN: Prospective randomised controlled trial. SETTING: Tertiary teaching hospital. POPULATION: One hundred and thirty-nine women with stage >or=2 prolapse according to the pelvic organ prolapse quantification (POP-Q) system requiring both anterior and posterior compartment repair. METHODS: Subjects were randomised to anterior and posterior vaginal repair with mesh augmentation (mesh group, n = 69) or traditional anterior and posterior colporrhaphy (no mesh group, n = 70). MAIN OUTCOME MEASURES: The primary outcome was the absence of POP-Q stage >or=2 prolapse at 12 months. Secondary outcomes were symptoms, quality-of-life outcomes and satisfaction with surgery. Complications were also reported. RESULTS: For subjects attending the 12-month review, success in the mesh group was 81.0% (51 of 63 subjects) compared with 65.6% (40/61) in the no mesh group and was not significantly different (P-value = 0.07). A high level of satisfaction with surgery and improvements in symptoms and quality-of-life data were observed at 12 months compared to baseline in both groups, but there was no significant difference in these outcomes between the two groups. Vaginal mesh exposure occurred in four women in the mesh group (5.6%). De novo dyspareunia was reported by five of 30 (16.7%) sexually active women in the mesh group and five of 33 (15.2%) in the no mesh group at 12 months. CONCLUSION: In this study, vaginal surgery augmented by mesh did not result in significantly less recurrent prolapse than traditional colporrhaphy 12 months following surgery.

"I'm obviously not dying so it's not something I need to sort out today": Considering hepatitis C treatment in the era of direct acting antivirals.

BACKGROUND: People who inject drugs are the group at greatest risk of hepatitis C virus (HCV) infection. The advent of new direct-acting antiviral (DAA) treatment provides opportunities for increased uptake of therapy. METHODS: We conducted in-depth interviews with thirty HCV positive participants from the SuperMIX cohort study. Interviews were transcribed, coded, and analysed for emerging themes and similarities between participants. General descriptions and critical interpretation of themes were generated and selective quotes extracted verbatim to best illustrate the critical themes. RESULTS: Participants described their experiences of living with HCV, their knowledge of HCV treatment accessibility, and information on the types of support ain themes: Understanding the need for treatment; Knowledge and framing of treatment access; and Support during treatment. CONCLUSION: The new, highly effective DAAs for the treatment of HCV are heralded as the potential beginning of HCV elimination, especially in settings where scale up is high. Our data from active PWID show that the availability of DAA medications in and of themselves is likely not to be enough to ensure that PWID will come forward for HCV treatment in sufficient numbers to drive elimination.

Vaginal surgery for pelvic organ prolapse using mesh and a vaginal support device.

OBJECTIVES: To describe a new surgical procedure for pelvic organ prolapse using mesh and a vaginal support device (VSD) and to report the results of surgery. DESIGN: A prospective observational study. SETTING: Two tertiary referral Urogynaecology practices. POPULATION: Ninety-five women with International Continence Society pelvic organ prolapse quantification stage 2 or more pelvic organ prolapse who underwent vaginal surgery using mesh augmentation and a VSD. METHODS: Surgery involved a vaginal approach with mesh reinforcement and placement of a VSD for 4 weeks. At 6 and 12 months, women were examined for prolapse recurrence, and visual analogue scales for satisfaction were completed. Women completed quality-of-life (QOL) questionnaires preoperatively and at 6 and 12 months. MAIN OUTCOME MEASURES: Objective success of surgery at 6 and 12 months following surgery. Secondary outcomes were subjective success, complications, QOL outcomes and patients' satisfaction. RESULTS: Objective success rate was 92 and 85% at 6 and 12 months, respectively. Subjective success rate was 91 and 87% at 6 and 12 months, respectively. New prolapse in nonrepaired compartments accounted for 7 of 12 (58%) failures at 12 months. Two of 4 mesh exposures required surgery. Sexual dysfunction was reported by 58% of sexually active women preoperatively and 23% at 12 months. QOL scores significantly improved at 12 months compared with baseline (P < 0.0001). CONCLUSION: Vaginal surgery using mesh and a VSD is an effective procedure for pelvic organ prolapse. However, further studies are required to establish the role of the surgery described in this study.

Evidence of niche partitioning among bacteria living on plastics, organic particles and surrounding seawaters.

Plastic pollution is widespread in ocean ecosystems worldwide, but it is unknown if plastic offers a unique habitat for bacteria compared to communities in the water column and attached to naturally-occurring organic particles. The large set of samples taken during the Tara-Mediterranean expedition revealed for the first time a clear niche partitioning between free-living (FL), organic particle-attached (PA) and the recently introduced plastic marine debris (PMD). Bacterial counts in PMD presented higher cell enrichment factors than generally observed for PA fraction, when compared to FL bacteria in the surrounding waters. Taxonomic diversity was also higher in the PMD communities, where higher evenness indicated a favorable environment for a very large number of species. Cyanobacteria were particularly overrepresented in PMD, together with essential functions for biofilm formation and maturation. The community distinction between the three habitats was consistent across the large-scale sampling in the Western Mediterranean basin. 'Plastic specific bacteria' recovered only on the PMD represented half of the OTUs, thus forming a distinct habitat that should be further considered for understanding microbial biodiversity in changing marine ecosystems.

Community-based provision of direct-acting antiviral therapy for hepatitis C: study protocol and challenges of a randomized controlled trial.

BACKGROUND: To achieve the World Health Organization hepatitis C virus (HCV) elimination targets, it is essential to increase access to treatment. Direct-acting antiviral (DAA) treatment can be provided in primary healthcare services (PHCS), improving accessibility, and, potentially, retention in care. Here, we describe our protocol for assessing the effectiveness of providing DAAs in PHCS, and the impact on the HCV care cascade. In addition, we reflect on the challenges of conducting a model of care study during a period of unprecedented change in HCV care and treatment. METHODS: Consenting patients with HCV infection attending 13 PHCS in Australia or New Zealand are randomized to receive DAA treatment at the local tertiary institution (standard care arm), or their PHCS (intervention arm). The primary endpoint is the proportion commenced on DAAs and cured. Treatment providers at the PHCS include: hepatology nurses, primary care practitioners, or, in two sites, a specialist physician. All PHCS offer opioid substitution therapy. DISCUSSION: The Prime Study is the first real-world, randomized, model of care study exploring the impact of community provision of DAA therapy on HCV-treatment uptake and cure. Although the study has faced challenges unique to this period of time characterized by changing treatment and service delivery, the data gained will be of critical importance in shaping health service policy that enables the elimination of HCV. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT02555475 . Registered on 15 September 2015.

Raf-1/bcl-2 phosphorylation: a step from microtubule damage to cell death.

Recent studies have shown that paclitaxel leads to activation of Raf-1 kinase and have suggested that this activation is essential for bcl-2 phosphorylation and apoptosis. In the present study, we demonstrate that, in addition to paclitaxel, other agents that interact with tubulin and microtubules also induce Raf-1/bcl-2 phosphorylation, whereas DNA-damaging drugs, antimetabolites, and alkylating agents do not. Activation of Raf-1 kinase by paclitaxel is linked to tubulin polymerization; the effect is blunted in paclitaxel-resistant cells, the tubulin of which does not polymerize following the addition of paclitaxel. In contrast, vincristine and vinblastine, drugs to which the paclitaxel-resistant cells retain sensitivity were able to bring about Raf-1 phosphorylation. The requirement for disruption of microtubules in this signaling cascade was strengthened further using paclitaxel analogues by demonstrating a correlation between tubulin polymerization, Raf-1/bcl-2 phosphorylation, and cytotoxicity. Inhibition of RNA or protein synthesis prevents Raf-1 activation and bcl-2 phosphorylation, suggesting that an intermediate protein(s) acts upstream of Raf-1 in this microtubule damage-activating pathway. A model is proposed that envisions a pathway of Raf-1 activation and bcl-2 phosphorylation following disruption of microtubular architecture, serving a role similar to p53 induction following DNA damage.

[Ru(phen)2dppz](2+) luminescence reveals nanoscale variation of polarity in the cyclodextrin cavity.

Phosphorylation of ß-cyclodextrin enhances binding with Ru(II)polypyridyl complexes, and promotes selectivity based on chirality and ligand hydrophobicity. For [Ru(phen)2dppz](2+), inclusion of dppz results in a dramatic increase in luminescence with multiple lifetimes. The sensitive response of photophysics to the environment reveals nanoscale variation of polarity.

RNA sequence evolution with secondary structure constraints: comparison of substitution rate models using maximum-likelihood methods.

We test models for the evolution of helical regions of RNA sequences, where the base pairing constraint leads to correlated compensatory substitutions occurring on either side of the pair. These models are of three types: 6-state models include only the four Watson-Crick pairs plus GU and UG; 7-state models include a single mismatch state that combines all of the 10 possible mismatches; 16-state models treat all mismatch states separately. We analyzed a set of eubacterial ribosomal RNA sequences with a well-established phylogenetic tree structure. For each model, the maximum-likelihood values of the parameters were obtained. The models were compared using the Akaike information criterion, the likelihood-ratio test, and Cox's test. With a high significance level, models that permit a nonzero rate of double substitutions performed better than those that assume zero double substitution rate. Some models assume symmetry between GC and CG, between AU and UA, and between GU and UG. Models that relaxed this symmetry assumption performed slightly better, but the tests did not all agree on the significance level. The most general time-reversible model significantly outperformed any of the simplifications. We consider the relative merits of all these models for molecular phylogenetics.

Redundant and non-functional guide RNA genes in Trypanosoma brucei are a consequence of multiple genes per minicircle.

The mitochondrial mRNA of the parasitic protozoa Trypanosoma brucei is extensively edited by the insertion, and occasional deletion, of uridine residues. The editing is mediated by over 200 guide RNAs (gRNAs) that are encoded in circular DNA molecules called minicircles. There are some 250 different types of minicircle, called classes, with each encoding several gRNAs. Sequencing of gRNAs and minicircles has revealed a surprising amount of both redundancy, where gRNAs from different minicircle classes edit exactly the same part of an mRNA, and non-functionality, where partial or no complementarity is found between gRNA and mRNA. How does this redundancy and non-functionality arise and persist? We propose the following. Minicircle classes that contain several functional gRNA genes can be lost from the population via drift and replaced by more minicircle classes that contain fewer functional gRNA genes, on the condition that the cells keep a full complement of functional gRNAs. We demonstrate this hypothesis in a computer simulation of a model of minicircle evolution. We show that this process leads to an increasing number of minicircle classes and inevitably to only one functional gRNA per minicircle. Moreover, we show that the genome contains more minicircle classes than is actually necessary for cell survival. We also analyse the available minicircle sequence data and conclude that T. brucei is at a transient stage in this process. In addition, ten new putative gRNAs have been discovered.

Synthesis and biological evaluation of 2-acyl analogues of paclitaxel (Taxol).

The anticancer drug paclitaxel (Taxol) has been converted to a large number of 2-debenzoyl-2-aroyl derivatives by three different methods. The bioactivities of the resulting analogues were determined in both tubulin polymerization and cytotoxicity assays, and several analogues with enhanced activity as compared with paclitaxel were discovered. Correlation of cytotoxicity in three cell lines with tubulin polymerization activity showed reasonable agreement. Among the cell lines examined, the closest correlation with antitubulin activity was observed with a human ovarian carcinoma cell line.

The mimetic transition: a simulation study of the evolution of learning by imitation.

Culturally transmitted ideas or memes must have had a large effect on the survival and fecundity of early humans. Those with better techniques of obtaining food and making tools, clothing and shelters would have had a substantial advantage. It has been proposed that memes can explain why our species has an unusually large brain and high cognitive ability: the brain evolved because of selection for the ability to imitate. This article presents an evolutionary model of a population in which culturally transmitted memes can have both positive and negative effects on the fitness of individuals. It is found that genes for increased imitative ability are selectively favoured. The model predicts that imitative ability increases slowly until a mimetic transition occurs where memes become able to spread like an epidemic. At this point there is a dramatic increase in the imitative ability, the number of memes known per individual and the mean fitness of the population. Selection for increased imitative ability is able to overcome substantial selection against increased brain size in some cases.