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Objective The Anti-Freaze-F (AFF) trial assessed the feasibility of conducting a definitive trial to determine whether intra-articular injection of adalimumab can reduce pain and improve function in people with pain-predominant early-stage frozen shoulder.Design Multicentre, randomised feasibility trial, with embedded qualitative study.Setting Four UK National Health Service (NHS) musculoskeletal and related physiotherapy services.Participants Adults ≥18 years with new episode of shoulder pain attributable to early-stage frozen shoulder.Interventions Participants were randomised (centralised computer generated 1:1 allocation) to either ultrasound-guided intra-articular injection of: (1) adalimumab (160 mg) or (2) placebo (saline (0.9% sodium chloride)). Participants and outcome assessors were blinded to treatment allocation. Second injection of allocated treatment (adalimumab 80 mg) or equivalent placebo was administered 2–3 weeks later.Primary feasibility objectives (1) Ability to screen and identify participants; (2) willingness of eligible participants to consent and be randomised; (3) practicalities of delivering the intervention; (4) SD of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months.Results Between 31 May 2022 and 7 February 2023, 156 patients were screened of whom 39 (25%) were eligible. The main reasons for ineligibility were other shoulder disorder (38.5%; n=45/117) or no longer in pain-predominant frozen shoulder (33.3%; n=39/117). Of the 39 eligible patients, nine (23.1%) consented to be randomised (adalimumab n=4; placebo n=5). The main reason patients declined was because they preferred receiving steroid injection (n=13). All participants received treatment as allocated. The mean time from randomisation to first injection was 12.3 (adalimumab) and 7.2 days (placebo). Completion rates for patient-reported and clinician-assessed outcomes were 100%.Conclusion This study demonstrated that current NHS musculoskeletal physiotherapy settings yielded only small numbers of participants, too few to make a trial viable. This was because many patients had passed the early stage of frozen shoulder or had already formulated a preference for treatment.Trial registration number ISRCTN 27075727, EudraCT 2021-03509-23, ClinicalTrials.gov NCT05299242 (REC 21/NE/0214).

Objectives To assess the feasibility of conducting a pragmatic, multicentre randomised controlled trial (RCT) to test the clinical and cost-effectiveness of an informal caregiver training programme to support the recovery of people following hip fracture surgery.Design Two-arm, multicentre, pragmatic, open, feasibility RCT with embedded qualitative study.Setting National Health Service (NHS) providers in five English hospitals.Participants Community-dwelling adults, aged 60 years and over, who undergo hip fracture surgery and their informal caregivers.Intervention Usual care: usual NHS care. Experimental: usual NHS care plus a caregiver–patient dyad training programme (HIP HELPER). This programme comprised three, 1 hour, one-to-one training sessions for a patient and caregiver, delivered by a nurse, physiotherapist or occupational therapist in the hospital setting predischarge. After discharge, patients and caregivers were supported through three telephone coaching sessions.Randomisation and blinding Central randomisation was computer generated (1:1), stratified by hospital and level of patient cognitive impairment. There was no blinding.Main outcome measures Data collected at baseline and 4 months post randomisation included: screening logs, intervention logs, fidelity checklists, acceptability data and clinical outcomes. Interviews were conducted with a subset of participants and health professionals.Results 102 participants were enrolled (51 patients; 51 caregivers). Thirty-nine per cent (515/1311) of patients screened were eligible. Eleven per cent (56/515) of eligible patients consented to be randomised. Forty-eight per cent (12/25) of the intervention group reached compliance to their allocated intervention. There was no evidence of treatment contamination. Qualitative data demonstrated the trial and HIP HELPER programme was acceptable.Conclusions The HIP HELPER programme was acceptable to patient–caregiver dyads and health professionals. The COVID-19 pandemic impacting on site’s ability to deliver the research. Modifications are necessary to the design for a viable definitive RCT.Trial registration number ISRCTN13270387.

Objectives: The Anti-Freaze-F trial will assess the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with pain predominant early stage frozen shoulder. Methods and analysis: We are conducting a multi-centre, randomised feasibility study, with an embedded qualitative sub-study. We will recruit adults ≥18 years with a new episode of shoulder pain attributable to early stage frozen shoulder, recruited from at least five UK NHS musculoskeletal and related physiotherapy services. Participants (n=84) will be randomised (centralised computer generated 1:1 allocation) to receive either: 1) intra-articular injection of anti-TNF (adalimumab 160mg) or 2) placebo injection (saline [0.9% sodium chloride]), both under ultrasound guidance. A second injection of the allocated treatment (adalimumab 80mg) or equivalent volume of placebo will be administered 2-3 weeks later. All participants will receive a physiotherapy advice leaflet providing education and advice about frozen shoulder and pain management. The primary feasibility objectives are: 1) the ability to screen and identify potential participants with pain predominant early stage frozen shoulder; 2) willingness of eligible participants to consent and be randomised to intervention; 3) practicalities of delivering the intervention, including time to first injection and number of participants receiving second injection; 4) standard deviation of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months from baseline in order to estimate the sample size for a definitive trial. We will also assess follow up rates and viability of patient-reported outcome measures and range of shoulder motion for a definitive trial. Research Ethics Committee approval (REC 21/NE/0214). Trial registration number: ISRCTN 27075727; EudraCT number: 2021-003509-23; ClinicalTrials.gov NCT05299242.

BackgroundJournal articles describing randomized controlled trials (RCTs) and systematic reviews with meta-analysis of RCTs are not optimally reported and often miss crucial details. This poor reporting makes assessing these studies’ risk of bias or reproducing their results difficult. However, the reporting quality of diet- and nutrition-related RCTs and meta-analyses has not been explored. ObjectiveWe aimed to assess the reporting completeness and identify the main reporting limitations of diet- and nutrition-related RCTs and meta-analyses of RCTs, estimate the frequency of reproducible research practices among these RCTs, and estimate the frequency of distorted presentation or spin among these meta-analyses. MethodsTwo independent meta-research studies will be conducted using articles published in PubMed-indexed journals. The first will include a sample of diet- and nutrition-related RCTs; the second will include a sample of systematic reviews with meta-analysis of diet- and nutrition-related RCTs. A validated search strategy will be used to identify RCTs of nutritional interventions and an adapted strategy to identify meta-analyses in PubMed. We will search for RCTs and meta-analyses indexed in 1 calendar year and randomly select 100 RCTs (June 2021 to June 2022) and 100 meta-analyses (July 2021 to July 2022). Two reviewers will independently screen the titles and abstracts of records yielded by the searches, then read the full texts to confirm their eligibility. The general features of these published RCTs and meta-analyses will be extracted into a research electronic data capture database (REDCap; Vanderbilt University). The completeness of reporting of each RCT will be assessed using the items in the CONSORT (Consolidated Standards of Reporting Trials), its extensions, and the TIDieR (Template for Intervention Description and Replication) statements. Information about practices that promote research transparency and reproducibility, such as the publication of protocols and statistical analysis plans will be collected. There will be an assessment of the completeness of reporting of each meta-analysis using the items in the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement and collection of information about spin in the abstracts and full-texts. The results will be presented as descriptive statistics in diagrams or tables. These 2 meta-research studies are registered in the Open Science Framework. ResultsThe literature search for the first meta-research retrieved 20,030 records and 2182 were potentially eligible. The literature search for the second meta-research retrieved 10,918 records and 850 were potentially eligible. Among them, random samples of 100 RCTs and 100 meta-analyses were selected for data extraction. Data extraction is currently in progress, and completion is expected by the beginning of 2023. ConclusionsOur meta-research studies will summarize the main limitation on reporting completeness of nutrition- or diet-related RCTs and meta-analyses and provide comprehensive information regarding the particularities in the reporting of intervention studies in the nutrition field. International Registered Report Identifier (IRRID)DERR1-10.2196/43537

Introduction Degenerative cervical myelopathy (DCM) is a common and disabling condition of symptomatic cervical spinal cord compression secondary to degenerative changes in spinal structures leading to a mechanical stress injury of the spinal cord. RECEDE-Myelopathy aims to test the disease-modulating activity of the phosphodiesterase 3/phosphodiesterase 4 inhibitor Ibudilast as an adjuvant to surgical decompression in DCM.Methods and analysis RECEDE-Myelopathy is a multicentre, double-blind, randomised, placebo-controlled trial. Participants will be randomised to receive either 60–100 mg Ibudilast or placebo starting within 10 weeks prior to surgery and continuing for 24 weeks after surgery for a maximum of 34 weeks. Adults with DCM, who have a modified Japanese Orthopaedic Association (mJOA) score 8–14 inclusive and are scheduled for their first decompressive surgery are eligible for inclusion. The coprimary endpoints are pain measured on a visual analogue scale and physical function measured by the mJOA score at 6 months after surgery. Clinical assessments will be undertaken preoperatively, postoperatively and 3, 6 and 12 months after surgery. We hypothesise that adjuvant therapy with Ibudilast leads to a meaningful and additional improvement in either pain or function, as compared with standard routine care.Study design Clinical trial protocol V.2.2 October 2020.Ethics and dissemination Ethical approval has been obtained from HRA—Wales.The results will be presented at an international and national scientific conferences and in a peer-reviewed journals.Trial registration number ISRCTN Number: ISRCTN16682024.

Introduction The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) reporting guideline establishes a minimum set of items to be reported in any randomised controlled trial (RCT) protocol. The Template for Intervention Description and Replication (TIDieR) reporting guideline was developed to improve the reporting of interventions in RCT protocols and results papers. Reporting completeness in protocols of diet or nutrition-related RCTs has not been systematically investigated. We aim to identify published protocols of diet or nutrition-related RCTs, assess their reporting completeness and identify the main reporting limitations remaining in this field.Methods and analysis We will conduct a meta-research study of RCT protocols published in journals indexed in at least one of six selected databases between 2012 and 2022. We have run a search in PubMed, Embase, CINAHL, Web of Science, PsycINFO and Global Health using a search strategy designed to identify protocols of diet or nutrition-related RCTs. Two reviewers will independently screen the titles and abstracts of records yielded by the search in Rayyan. The full texts will then be read to confirm protocol eligibility. We will collect general study features (publication information, types of participants, interventions, comparators, outcomes and study design) of all eligible published protocols in this contemporary sample. We will assess reporting completeness in a randomly selected sample of them and identify their main reporting limitations. We will compare this subsample with the items in the SPIRIT and TIDieR statements. For all data collection, we will use data extraction forms in REDCap. This protocol is registered on the Open Science Framework (DOI: 10.17605/OSF.IO/YWEVS).Ethics and dissemination This study will undertake a secondary analysis of published data and does not require ethical approval. The results will be disseminated through journals and conferences targeting stakeholders involved in nutrition research.

Objective The Getting Recovery Right After Neck Dissection (GRRAND) intervention is a physiotherapy programme for patients with head and neck cancer who have undergone neck dissection. The aim of this qualitative study was to understand if the intervention was useful, acceptable and whether it was feasible to conduct a randomised controlled trial (RCT).Design This qualitative study was embedded within the GRRAND-Feasibility (GRRAND-F) Study.Setting Participants were recruited from four acute National Health Service hospitals in England between 2020 and 2021.Participants We interviewed four usual care and four intervention patient-participants from a single study site (Oxford). Six were male, two were female. All were white British ethnicity. We interviewed two physiotherapists from Oxford who delivered the GRRAND-F intervention, and physiotherapists from Birmingham, Poole and Norwich who were trained to deliver the intervention but were not able to deliver it within the study time frame.Results The analysis identified five themes: (1) Acceptability, (2) Adherence, (3) Outcomes, (4) Feasibility and (5) Stand-alone themes (prehabilitation, video consultations, healthcare use).Patient-participants and physiotherapist-participants agreed that usual care was not meeting patients’ rehabilitation needs. The GRRAND intervention provided biopsychosocial support. In comparison to the usual care group, patient-participants who received the intervention were more confident that they could perform rehabilitation exercises and were more motivated to engage in long-term adaptive behaviour change. Physiotherapists felt they needed more administrative support to participate in an RCT.Conclusion Participants felt that usual care was insufficient. GRRAND provided much needed, biopsychosocial support to patients. Participants were supportive that it would be feasible to test GRRAND in an RCT.Trial registration number ISRCTN11979997.

Objective To test the effectiveness of a behaviour change physiotherapy intervention to increase physical activity compared with usual rehabilitation after total hip replacement (THR) or total knee replacement (TKR).Design Multicentre, pragmatic, two-arm, open, randomised controlled, superiority trial.Setting National Health Service providers in nine English hospitals.Participants 224 individuals aged ≥18 years, undergoing a primary THR or TKR deemed ‘moderately inactive’ or ‘inactive’.Intervention Participants received either six, 30 min, weekly, group-based exercise sessions (usual care) or the same six weekly, group-based, exercise sessions each preceded by a 30 min cognitive behaviour discussion group aimed at challenging barriers to physical inactivity following surgery (experimental).Randomisation and blinding Initial 75 participants were randomised 1:1 before changing the allocation ratio to 2:1 (experimental:usual care). Allocation was based on minimisation, stratifying on comorbidities, operation type and hospital. There was no blinding.Main outcome measures Primary: University of California Los Angeles (UCLA) Activity Score at 12 months. Secondary: 6 and 12-month assessed function, pain, self-efficacy, kinesiophobia, psychological distress and quality of life.Results Of the 1254 participants assessed for eligibility, 224 were included (139 experimental: 85 usual care). Mean age was 68.4 years (SD: 8.7), 63% were women, 52% underwent TKR. There was no between-group difference in UCLA score (mean difference: −0.03 (95% CI −0.52 to 0.45, p=0.89)). There were no differences observed in any of the secondary outcomes at 6 or 12 months. There were no important adverse events in either group. The COVID-19 pandemic contributed to the reduced intended sample size (target 260) and reduced intervention compliance.Conclusions There is no evidence to suggest attending usual care physiotherapy sessions plus a group-based behaviour change intervention differs to attending usual care physiotherapy alone. As the trial could not reach its intended sample size, nor a proportion of participants receive their intended rehabilitation, this should be interpreted with caution.Trial registration number ISRCTN29770908.

Objectives: The Anti-Freaze-F trial will assess the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with pain predominant early stage frozen shoulder. Methods and analysis: We are conducting a multi-centre, randomised feasibility study, with an embedded qualitative sub-study. We will recruit adults ≥18 years with a new episode of shoulder pain attributable to early stage frozen shoulder, recruited from at least five UK NHS musculoskeletal and related physiotherapy services. Participants (n=84) will be randomised (centralised computer generated 1:1 allocation) to receive either: 1) intra-articular injection of anti-TNF (adalimumab 160mg) or 2) placebo injection (saline [0.9% sodium chloride]), both under ultrasound guidance. A second injection of the allocated treatment (adalimumab 80mg) or equivalent volume of placebo will be administered 2-3 weeks later. All participants will receive a physiotherapy advice leaflet providing education and advice about frozen shoulder and pain management. The primary feasibility objectives are: 1) the ability to screen and identify potential participants with pain predominant early stage frozen shoulder; 2) willingness of eligible participants to consent and be randomised to intervention; 3) practicalities of delivering the intervention, including time to first injection and number of participants receiving second injection; 4) standard deviation of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months from baseline in order to estimate the sample size for a definitive trial. We will also assess follow up rates and viability of patient-reported outcome measures and range of shoulder motion for a definitive trial. Research Ethics Committee approval (REC 21/NE/0214). Trial registration number: ISRCTN 27075727; EudraCT number: 2021-003509-23; ClinicalTrials.gov NCT05299242.

Objectives To explore the experiences and perceptions of trial participants and healthcare professionals in the UK Frozen Shoulder Trial (UK FROST), a multicentre randomised controlled trial that compared manipulation under anaesthesia (MUA), arthroscopic capsular release (ACR) with a 12-week early structured physiotherapy programme (ESP) in people with unilateral frozen shoulder referred to secondary care.Design Nested qualitative study with semistructured interviews. We used constant comparison method to develop our themes.Setting This qualitative study was nested within the UK FROST.Participants 44 trial participants (ESP: 14; MUA: 15; ACR: 15), and 8 surgeons and 8 physiotherapists who delivered the treatments in the trial.Results Trial participants found UK FROST treatments acceptable and satisfactory in terms of content, delivery and treatment benefits. Participants in all arms experienced improvements in pain, shoulder movements, and function. Participants said they would choose the same treatment that they received in the trial.Surgeons and physiotherapists felt that the content and delivery of UK FROST treatments was not significantly different to their routine practice except for the additional number of physiotherapy sessions offered in the trial. They had mixed feelings about the effectiveness of UK FROST treatments. Both stressed the value of including hydrodilatation as a comparator of other treatment options. Physiotherapists raised concerns about the capacity to deliver the number of UK FROST physiotherapy sessions in routine clinical settings.Shared perceptions of trial participants, surgeons and physiotherapists were: (1) Pain relief and return of shoulder movements and function are important outcomes and (2) Adherence to exercises leads to better outcomes.Conclusion In general, our findings indicated that trial participants, and surgeons and physiotherapists who delivered the treatments had positive experiences and perceptions in the UK FROST. Early qualitative investigations to explore the feasibility of delivering treatments in real-world settings are suggested in future trials in the frozen shoulder.Trial registration number International Standard Randomised Controlled Trial Register, ID: ISRCTN48804508. Registered on 25 July 2014; Results

BackgroundPlacebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions.Methods and findingsWe developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator.ConclusionsWe encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.

Introduction While total hip replacement (THR) and total knee replacement (TKR) successfully reduce pain associated with chronic joint pathology, this infrequently translates into increased physical activity. This is a challenge given that over 50% of individuals who undergo these operations are physically inactive and have medical comorbidities such as hypertension, heart disease, diabetes and depression. The impact of these diseases can be reduced with physical activity. This trial aims to investigate the effectiveness of a behaviour change physiotherapy intervention to increase physical activity compared with usual rehabilitation after THR or TKR.Methods and analysis The PEP-TALK trial is a multicentre, open-labelled, pragmatic randomised controlled trial. 260 adults who are scheduled to undergo a primary unilateral THR or TKR and are moderately inactive or inactive, with comorbidities, will be recruited across eight sites in England. They will be randomised post-surgery, prior to hospital discharge, to either six, 30 min weekly group-based exercise sessions (control), or the same six weekly, group-based, exercise sessions each preceded by a 30 min cognitive behaviour approach discussion group. Participants will be followed-up to 12 months by postal questionnaire. The primary outcome is the University of California, Los Angeles (UCLA) Physical Activity Score at 12 months. Secondary outcomes include: physical function, disability, health-related quality of life, kinesiophobia, perceived pain, self-efficacy and health resource utilisation.Ethics and dissemination Research ethics committee approval was granted by the NRES Committee South Central (Oxford B - 18/SC/0423). Dissemination of results will be through peer-reviewed, scientific journals and conference presentations.Trial registration number ISRCTN29770908.

Dupuytren’s disease is a common fibrotic condition of the hand affecting 4% of the population and causes the fingers to curl irreversibly into the palm. It has a strong familial tendency, there is no approved treatment for early stage disease, and patients with established digital contractures are most commonly treated by surgery. This is associated with prolonged recovery, and less invasive techniques have high recurrence rates. The myofibroblasts, the cells responsible for the excessive matrix deposition and contraction, are aggregated in nodules. Using excised diseased and control human tissue, we found that immune cells interspersed amongst the myofibroblasts secrete cytokines. Of these, only tumour necrosis factor (TNF) promoted the development of myofibroblasts. The clinically approved anti-TNF agents led to inhibition of the myofibroblast phenotype in vitro. This clinical trial is designed to assess the efficacy of the anti-TNF agent adalimumab on participants with early disease. The first part is a dose-ranging study where nodules of participants already scheduled for surgery will be injected with either placebo (saline) or varying doses of adalimumab. The excised tissue will then be analysed for markers of myofibroblast activity. The second part of the study will recruit participants with early stage disease. They will be randomised 1: 1 to receive either adalimumab or placebo at 3 month intervals over 1 year and will then be followed for a further 6 months. Outcome measures will include nodule hardness, size and disease progression. The trial will also determine the cost-effectiveness of adalimumb treatment for this group of participants.

BackgroundThere are no disease-modifying treatments for dementia. There is also no consensus on disease modifying outcomes. We aimed to produce the first evidence-based consensus on core outcome measures for trials of disease modification in mild-to-moderate dementia.Methods and findingsWe defined disease-modification interventions as those aiming to change the underlying pathology. We systematically searched electronic databases and previous systematic reviews for published and ongoing trials of disease-modifying treatments in mild-to-moderate dementia. We included 149/22,918 of the references found; with 81 outcome measures from 125 trials. Trials involved participants with Alzheimer's disease (AD) alone (n = 111), or AD and mild cognitive impairment (n = 8) and three vascular dementia. We divided outcomes by the domain measured (cognition, activities of daily living, biological markers, neuropsychiatric symptoms, quality of life, global). We calculated the number of trials and of participants using each outcome. We detailed psychometric properties of each outcome. We sought the views of people living with dementia and family carers in three cities through Alzheimer's society focus groups. Attendees at a consensus conference (experts in dementia research, disease-modification and harmonisation measures) decided on the core set of outcomes using these results. Recommended core outcomes were cognition as the fundamental deficit in dementia and to indicate disease modification, serial structural MRIs. Cognition should be measured by Mini Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive Subscale. MRIs would be optional for patients. We also made recommendations for measuring important, but non-core domains which may not change despite disease modification.LimitationsMost trials were about AD. Specific instruments may be superseded. We searched one database for psychometric properties.InterpretationThis is the first review to identify the 81 outcome measures the research community uses for disease-modifying trials in mild-to-moderate dementia. Our recommendations will facilitate designing, comparing and meta-analysing disease modification trials in mild-to-moderate dementia, increasing their value.Trial registrationPROSPERO no. CRD42015027346.

Genome and epigenome integrity in eukaryotes depends on the proper coupling of histone deposition with DNA synthesis. This process relies on the evolutionary conserved histone chaperone CAF-1 for which the links between structure and functions are still a puzzle. While studies of the Saccharomyces cerevisiae CAF-1 complex enabled to propose a model for the histone deposition mechanism, we still lack a framework to demonstrate its generality and in particular, how its interaction with the polymerase accessory factor PCNA is operating. Here, we reconstituted a complete SpCAF-1 from fission yeast. We characterized its dynamic structure using NMR, SAXS and molecular modeling together with in vitro and in vivo functional studies on rationally designed interaction mutants. Importantly, we identify the unfolded nature of the acidic domain which folds up when binding to histones. We also show how the long KER helix mediates DNA binding and stimulates SpCAF-1 association with PCNA. Our study highlights how the organization of CAF-1 comprising both disordered regions and folded modules enables the dynamics of multiple interactions to promote synthesis-coupled histone deposition essential for its DNA replication, heterochromatin maintenance, and genome stability functions.

Gay and bisexual men (GBM) report higher rates of methamphetamine use compared to heterosexual men, and thus have a heightened risk of developing problems from their use. We examined treatment outcomes among GBM clients receiving outpatient counseling at a lesbian, gay, bisexual, transgender and intersex (LGBTI)-specific, harm reduction treatment service in Sydney, Australia. GBM receiving treatment for methamphetamine use from ACON's Substance Support Service between 2012-15 (n = 101) were interviewed at treatment commencement, and after 4 sessions (n = 60; follow-up 1) and 8 sessions (n = 32; follow-up 2). At each interview, clients completed measures of methamphetamine use and dependence, other substance use, injecting risk practices, psychological distress and quality of life. The median age of participants was 41 years and 56.4% identified as HIV-positive. Participants attended a median of 5 sessions and attended treatment for a median of 112 days. There was a significant reduction in the median days of methamphetamine use in the previous 4 weeks between baseline (4 days), follow-up 1 (2 days) and follow-up 2 (2 days; p = .001). There was a significant reduction in the proportion of participants reporting methamphetamine dependence between baseline (92.1%), follow-up 1 (78.3%) and follow-up 2 (71.9%, p < .001). There were also significant reductions in psychological distress (p < .001), and significant improvements in quality of life (p < .001). Clients showed reductions in methamphetamine use and improved psychosocial functioning over time, demonstrating the potential effectiveness of a LGBTI-specific treatment service.

Rad52 is a key player in homologous recombination (HR), a DNA repair pathway that is dedicated to double strand breaks repair and recovery of perturbed replication forks. Here we show that fission yeast Rad52 homologue is phosphorylated when S phase cells are exposed to ROS inducers such as ultraviolet A radiation or hydrogen peroxide, but not to ultraviolet C or camptothecin. Phosphorylation does not depend on kinases Chk1, Rad3, Tel1 or Cdc2, but depends on a functional stress activated protein kinase (SAPK) pathway and can be partially prevented by anti-oxidant treatment. Indeed, cells lacking Sty1, the major fission yeast MAP kinase of the SAPK pathway, do not display Rad52 phosphorylation and have UVA induced Rad52 foci that persist longer if compared to wild type cells. In addition, spontaneous intrachromosomal HR is diminished in cells lacking Sty1 and, more precisely, gene conversion is affected. Moreover, HR induced by site-specific arrest of replication forks is twice less efficient in cells that do not express Sty1. Importantly, impairing HR by deletion of the gene encoding the recombinase Rhp51 leads to Sty1 dependent Rad52 phosphorylation. Thus, SAPK pathway impinges on early step of HR through phosphorylation of Rad52 in cells challenged by oxidative stress or lacking Rhp51 and is required to promote spontaneous gene conversion and recovery from blocked replication forks.

In mammals, plasma amino acid concentrations are markedly affected by dietary or pathological conditions. It has been well established that amino acids are involved in the control of gene expression. Up to now, all the information concerning the molecular mechanisms involved in the regulation of gene transcription by amino acid availability has been obtained in cultured cell lines. The present study aims to investigate the mechanisms involved in transcriptional activation of the TRB3 gene following amino acid limitation in mice liver. The results show that TRB3 is up-regulated in the liver of mice fed a leucine-deficient diet and that this induction is quickly reversible. Using transient transfection and chromatin immunoprecipitation approaches in hepatoma cells, we report the characterization of a functional Amino Acid Response Element (AARE) in the TRB3 promoter and the binding of ATF4, ATF2 and C/EBPβ to this AARE sequence. We also provide evidence that only the binding of ATF4 to the AARE plays a crucial role in the amino acid-regulated transcription of TRB3. In mouse liver, we demonstrate that the GCN2/eIF2α/ATF4 pathway is essential for the induction of the TRB3 gene transcription in response to a leucine-deficient diet. Therefore, this work establishes for the first time that the molecular mechanisms involved in the regulation of gene transcription by amino acid availability are functional in mouse liver.

Prostaglandin F(2alpha) (PGF(2alpha)), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF(2alpha) synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF(2alpha) biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF(2alpha) but expressed different biosynthetic isozymes. In chromaffin cells, PGF(2alpha) secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF(2alpha) secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF(2alpha) release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF(2alpha) receptor was only detected in chromaffin cells, making medulla the primary target of PGF(2alpha) action. By comparing PGF(2alpha)-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF(2alpha) repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF(2alpha) may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal.