Endometriosis - a painful disease.

PURPOSE OF REVIEW: This review looks to overview advances in endometriosis-associated pain, both in understanding the pain mechanisms involved and increasing treatment options with well designed clinical trials and meta-analyses. RECENT FINDINGS: Our understanding of endometriosis-associated pain has progressed from a purely nociceptive model to an awareness that both neuropathic and nociplastic mechanisms can be present for some people with endometriosis. Clinical trials and meta-analyses have demonstrated efficacy of surgical treatments and hormonal therapies. It is notable that currently, the basic science and clinical trials are not cross-fertilising. SUMMARY: Following growth in other areas of chronic pain, there have been significant advances in our understanding of endometriosis-associated pain. However, there remains lots to explore and we are currently a long way from our goal of timely personalized holistic multidisciplinary treatment for all sufferers of endometriosis-associated pain.

Comprehensive quantitative sensory testing shows altered sensory function in women with chronic pelvic pain: results from the Translational Research in Pelvic Pain (TRiPP) Study.

ABSTRACT: Chronic pelvic pain (CPP), despite its high prevalence, is still relatively poorly understood mechanistically. This study, as part of the Translational Research in Pelvic Pain (TRiPP) project, has used a full quantitative sensory testing (QST) paradigm to profile n = 85 women with and without CPP (endometriosis or bladder pain specifically). We used the foot as a control site and abdomen as the test site. Across 5 diagnostically determined subgroups, we found features which are common across different aetiologies, eg, gain of function in pressure pain threshold (PPT) when assessing responses from the lower abdomen or pelvis (referred pain site). However, disease-specific phenotypes were also identified, eg, greater mechanical allodynia in endometriosis, despite there being large heterogeneities within diagnostic groups. The most common QST sensory phenotype was mechanical hyperalgesia (>50% across all the groups). A "healthy' sensory phenotype was seen in <7% of CPP participants. Specific QST measures correlated with sensory symptoms assessed by the painDETECT questionnaire (pressure-evoked pain [painDETECT] and PPT [QST] [ r = 0.47, P < 0.001]; mechanical hyperalgesia (painDETECT) and mechanical pain sensitivity [MPS from QST] [ r = 0.38, P = 0.009]). The data suggest that participants with CPP are sensitive to both deep tissue and cutaneous inputs, suggesting that central mechanisms may be important in this cohort. We also see phenotypes such as thermal hyperalgesia, which may be the result of peripheral mechanisms, such as irritable nociceptors. This highlights the importance of stratifying patients into clinically meaningful phenotypes, which may have implications for the development of better therapeutic strategies for CPP.

Mindfulness-based intervention in patients with persistent pain in chest (MIPIC) of non-cardiac cause: a feasibility randomised control study.

OBJECTIVE: The study evaluated the feasibility of mindfulness-based cognitive therapy (MBCT) in patients with non-cardiac chest pain by assessing their willingness to participate and adhere to the programme, and for these data to help further refine the content of MBCT for chest pain. PATIENTS AND METHODS: This prospective 2:1 randomised controlled trial compared the intervention of adapted MBCT as an addition to usual care with just usual care in controls. Among 573 patients who attended the rapid access chest pain clinic over the previous 12 months and were not diagnosed with a cardiac cause but had persistent chest pain were invited. The intervention was a 2-hour, weekly, online guided 8-week MBCT course. Compliance with attendance and the home practice was recorded. Enrolled patients completed the Seattle angina questionnaire (SAQ), Hospital Anxiety and Depression Scale, Cardiac Anxiety Questionnaire, Five-Facet Mindfulness Questionnaire, and Euro Quality of Life-5 Dimensions-5 Level at baseline assessment and after 8-week period. RESULTS: Persistent chest pain was reported by 114 patients. Of these, 33 (29%) patients with a mean age of 54.2 (±12.2) years and 68% women, consented to the study. Baseline questionnaires revealed mild physical limitation (mean SAQ, 76.8±25), high levels of anxiety (76%) and depression (53%), modest cardiac anxiety (CAQ,1.78±0.61) and mindfulness score (FFMQ, 45.5±7.3). Six patients subsequently withdrew due to bereavement, caring responsibilities and ill health. Of the remaining 27 participants, 18 in the intervention arm attended an average of 5 sessions with 61% attending ≥6 sessions. Although not statistically powered, the study revealed a significant reduction in general anxiety, improved mindfulness and a trend towards improvement in SAQ scores in the intervention arm. CONCLUSION: One-third of patients with persistent non-cardiac chest pain were willing to participate in mindfulness-based therapy. An improvement in anxiety and mindfulness was detected in this feasibility study. A larger trial is required to demonstrate improvement in chest pain symptoms.

TikTok: An Opportunity for Antibiotic Education?

Health information and misinformation on social media have become a growing concern for the medical community. Antimicrobial resistance continues to advance, threatening public health and safety. TikTok, a popular social media platform, provides an avenue for providers to educate patients on clinical topics and medication use. As leaders in patient education and counseling, pharmacists are equipped to provide trustworthy information on TikTok and other platforms. Pharmacists can thus advance the practice of pharmacy and build rapport with patients through a new medium. Current health-related videos on TikTok have not been robustly evaluated for quality and reliability. This study evaluates antibiotic-related content from healthcare providers and non-healthcare providers on TikTok for balance, reliability, and quality using the DISCERN score. Introduction: Antimicrobial resistance is increasing at an alarming rate. Patient education is a critical component of both stewardship and combating health misinformation. TikTok is a video-sharing social media platform with 1 billion monthly users and contains videos that discuss health information. The objective of this study was to evaluate antibiotic-themed TikTok videos for their validity and reliability. Methods: In March 2021, a search on TikTok using the term "antibiotics" was performed and the top 300 consecutive videos were identified. The following data was collected for each video: number of likes, associated disease state, medications, educational aim, mention of COVID-19, and if performed by a healthcare professional (HCP). Non-English language videos were excluded. The DISCERN score was used to evaluate all videos for reliability. Chi-square and Mann-Whitney U were used for statistical analysis. A p-value less than .05 was considered statistically significant. Results: The first 300 consecutive videos were assessed using the DISCERN score for validity. Of the 300 videos, the majority (n=224) were created by non-health care professionals (non-HCPs). The number of "likes" per video ranged from 1 like to 2 million likes with a mean of 34,949 ± 143,482. Videos produced by HCPs were significantly more valid and reliable (mean DISCERN score of 1.65 vs 1.17, p <0.00001) than non-HCPs. They were found to be more relevant (p<0.00001), have clearer aims (p<0.00001), and were more balanced/unbiased (p=0.00188). Videos created by HCPs were more likely to have an educational focus (p<0.0001). There was no difference between groups in clarity of sources utilized or risk/benefits discussed of each treatment. Across all videos, the most common disease states mentioned were urinary tract infection, skin and soft tissue infection, upper respiratory tract infection, and dental infection. Herbal or supplement products, penicillins, and sulfa antibiotics were the most commonly discussed medications. Conclusions: Videos created by HCPs were significantly more valid and reliable than those created by non-HCPs. The videos created by HCPs were also more likely to have clear aims and be more relevant. However, the majority of the videos evaluated were created by non-HCPs. It may be beneficial for HCPs to provide informative TikTok videos that are valid and reliable for patient education.

The Global Impact of COVID-19 on the Care of People With Endometriosis.

Endometriosis is a chronic condition affecting ~10% of women globally. Little is known about the impact of the coronavirus disease 2019 (COVID-19) pandemic on their care. This brief report is aimed to explore the impact of COVID-19 on the care of people with endometriosis around the world, their priorities in relation to their clinical care during and coming out of the pandemic, and whether they believed that endometriosis makes them more vulnerable to COVID-19. An internet-based survey collected data in five languages between May 11, 2020, and June 8, 2020. Only participants with a surgical or radiological diagnosis of endometriosis aged 18 years or over were included. A total of 6,729 eligible respondents completed the survey with 80.7% [95% CI (79.7, 81.6)] reporting a negative impact on their care. This included difficulties obtaining medication (20.3%), cancelled/postponed gynaecology appointments (50.0%), and cancelled/postponed procedures (37.2%). More than half worried that their endometrioses make them more vulnerable to COVID-19 [54.2%; 95% CI (53.0, 55.4)]. The top three priorities were remarkably consistent around the world: contact with gynaecologists, knowing when procedures would be performed, and support with mental health (20.3% prioritising this aspect during the pandemic and 13.0% as restrictions begin to ease). This study shows the substantial impact the COVID-19 pandemic has had on people with endometriosis and describes how they would like care prioritised moving forwards. The findings regarding significant support needs for mental health add further weight to the growing recognition of attending to such issues as part of good patient-centred care.

Strategies for Students to Optimize Their Learning Experience in Virtual Patient-Care Settings.

Authors respond to the article by Dr. Karaoui and colleagues from the November issue of volume 35 in this journal that describes challenges in pharmacy education due to the COVID-19 pandemic. The authors are students who provide strategies for student success while on virtual introductory or Advanced Pharmacy Practice Experiences during COVID-19.

Placenta accreta spectrum disorders - Peri-operative management: The role of the anaesthetist.

The incidence of placenta accreta spectrum (PAS) is increasing and will become more commonly encountered by obstetric anaesthetists in the elective and emergency settings. Significant maternal and neonatal morbidity is associated with these disorders, and hence it is important for anaesthetists to have early involvement in perioperative planning. Major haemorrhage should be anticipated and requires robust perioperative preparation including Patient Blood Management (PBM) and use of intraoperative strategies for haemorrhage management wherever possible. Several institutions have demonstrated good outcomes with regional anaesthesia alone, but the choice of anaesthetic technique requires individualised planning considering patient, anaesthetic and surgical factors. Optimisation of postoperative analgesia needs additional consideration; it is key to good recovery, minimising the impact on quality of life and reducing the risk of persistent post-surgical pain. Further research is required to ascertain the optimal multi-modal analgesic regime including the role of peripheral nerve blockade.

A randomized clinical trial of mindfulness-based cognitive therapy for women with irritable bowel syndrome-Effects and mechanisms.

OBJECTIVE: Irritable bowel syndrome (IBS) is a chronic disorder of brain-gut interaction. Previous studies suggest that mindfulness could be therapeutic for IBS patients, however no study has evaluated the effects of mindfulness-based cognitive therapy adapted for patients with IBS (MBCT-IBS). A 6-week MBCT-IBS course was designed to reduce symptoms and increase quality of life. This study aimed to evaluate the effects of MBCT-IBS and to investigate its therapeutic mechanisms in a randomized controlled trial. METHOD: Sixty-seven female patients with IBS were randomized to MBCT-IBS (MG; n = 36) or a waitlist (WL; n = 31) control condition. Patients completed standardized self-report measures of IBS symptom severity, IBS quality of life, maladaptive illness cognitions (catastrophizing, visceral anxiety sensitivity) and mindfulness at baseline, after 2 treatment sessions, at posttreatment, and at 6-week follow-up. Self-referential processing of illness and health was measured with an implicit association test (IAT). RESULTS: The MG reported significantly greater reductions in IBS symptoms (p = .003) and improvements in quality of life (p < .001) at follow-up compared with the WL. Changes in visceral anxiety sensitivity and pain catastrophizing at posttreatment and reductions in the IAT-score after 2 sessions combined with increases in nonjudgmental awareness at posttreatment mediated reductions in IBS symptoms. CONCLUSIONS: MBCT-IBS has the potential to reduce IBS symptoms and increase quality of life. MBCT-IBS may exert its effect on IBS symptoms via reducing maladaptive illness cognitions and activating changes in self-processing (reducing biases in self-referent processing of illness and health and increasing nonjudgmental awareness). (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Shame, social deprivation, and the quality of the voice-hearing relationship.

OBJECTIVES: Many individuals hold different beliefs about the voices that they hear and have distinct relationships with them, the nature of which may determine the distress experienced. Understanding what factors contribute to these beliefs and relationships and consequently the resulting distress is important. The current research examined whether shame and social deprivation, in a sample of adult voice-hearers, were related to the relationships that individuals had with their voices or the beliefs that they held about them. DESIGN: The study utilized a cross-sectional, Internet-based design. METHODS: Eighty-seven adult voice-hearers from England were recruited to the online survey. Participants completed measures regarding shame, beliefs about voices, and relationships with voices and provided demographic information and postcodes that were used to refer to Index of Multiple Deprivation data. RESULTS: Social deprivation and shame were not associated. Shame was positively associated with variables describing negative voice-hearing beliefs/relationships but not positive voice-hearing beliefs/relationships. Principal component analysis on the eight voice-hearing variables yielded two components related to positive and negative voice-hearing qualities. A multiple regression conducted on the two components identified that shame was only associated with negative voice-hearing qualities. CONCLUSIONS: The results suggest that therapies that target shame may be helpful when working with negative voice-hearing beliefs and relationships. Future research should utilize experimental or longitudinal designs to examine the direction of the relationship. PRACTITIONER POINTS: The results contribute to the limited research evidence available regarding the relationship between shame and voice-hearing. The results suggest the utility of psychological therapies that focus on shame such as compassion-focused therapy and that conceptualize voices interpersonally such as cognitive analytic therapy. No conclusions can be made regarding causation. The sample size was relatively small, and results cannot be generalized to other areas of the United Kingdom. Future research should utilize experimental and longitudinal designs to examine the impact of shame on voice-hearing experiences and to examine other factors that may predict shame.

Feasibility and acceptability of suicide prevention therapy on acute psychiatric wards: randomised controlled trial.

BACKGROUND: Suicidal behaviour is common in acute psychiatric wards resulting in distress, and burden for patients, carers and society. Although psychological therapies for suicidal behaviour are effective in out-patient settings, there is little research on their effectiveness for in-patients who are suicidal.AimsOur primary objective was to determine whether cognitive-behavioural suicide prevention therapy (CBSP) was feasible and acceptable, compared with treatment as usual (TAU) for in-patients who are suicidal. Secondary aims were to assess the impact of CBSP on suicidal thinking, behaviours, functioning, quality of life, service use, cost-effectiveness and psychological factors associated with suicide. METHOD: A single-blind pilot randomised controlled trial comparing TAU to TAU plus CBSP in in-patients in acute psychiatric wards who are suicidal (the Inpatient Suicide Intervention and Therapy Evaluation (INSITE) trial, trial registration: ISRCTN17890126). The intervention consisted of TAU plus up to 20 CBSP sessions, over 6 months continuing in the community following discharge. Participants were assessed at baseline and at 6 weeks and 6 months post-baseline. RESULTS: A total of 51 individuals were randomised (27 to TAU, 24 to TAU plus CBSP) of whom 37 were followed up at 6 months (19 in TAU, 18 in TAU plus CBSP). Engagement, attendance, safety and user feedback indicated that the addition of CBSP to TAU for in-patients who are acutely suicidal was feasible and acceptable while on in-patient wards and following discharge. Economic analysis suggests the intervention could be cost-effective.DiscussionPsychological therapy can be delivered safely to patients who are suicidal although modifications are required for this setting. Findings indicate a larger, definitive trial should be conducted.Declaration of interestThe trial was hosted by Greater Manchester Mental health NHS Trust (formerly, Manchester Mental Health and Social Care NHS Trust). The authors are affiliated to the University of Manchester, Greater Manchester Mental Health Foundation Trust, Lancashire Care NHS Foundation trust and the Manchester Academic Health Sciences Centre. Y.A. is a trustee for a North-West England branch of the charity Mind.

Current trends in the management of canine traumatic brain injury: An Internet-based survey.

This study characterized trends in management of canine traumatic brain injury (TBI) among 182 small animal veterinarians grouped as follows: Board-certified specialists at a veterinary teaching hospital (BCS-VTH), Board-certified specialists in private practice (BCS-PP), non-specialists at a teaching hospital (DVM-VTH), and non-specialists in private practice (DVM-PP). The BCS-VTH, BSC-PP, and DVM-VTH groups were more comfortable using the modified Glasgow Coma Scale (MGCS) than the DVM-PP group (P < 0.001, P < 0.001, and P = 0.009, respectively). All respondents chose the following diagnostics most frequently: packed cell volume/total solids (95.6%), blood glucose (96.7%), and blood pressure (95.0%). The DVM-VTH group chose the following more frequently than the DVM-PP group: computed tomography (19.4% versus 4.5%; P = 0.027), venous or arterial blood gas (83.9% versus 46.3%; P < 0.001), electrocardiography (71.0% versus 44.8%; P = 0.018), lactate (87.1% versus 59.7%; P = 0.009), and brief thoracic ultrasound (87.1% versus 62.7%; P = 0.017). BCS-PP chose hypertonic saline more frequently than DVM-PP (94.1% versus 74.6%; P = 0.005). The DVM-PP group chose corticosteroid therapy and anticonvulsant therapy more frequently than BCS-PP (10.4% versus 0.0%; P = 0.019; 73.1% versus 43.1%; P = 0.004, respectively). This study highlights variability in management of canine TBI.

Tendances actuelles dans la gestion des traumatismes cérébraux canins : sondage sur Internet. Cette étude a caractérisé les tendances dans la gestion des traumatismes cérébraux canins (TC) parmi 182 médecins vétérinaires pour petits animaux regroupés de la façon suivante : spécialistes agréés par un conseil dans un hôpital d'enseignement vétérinaire (BCS-VTH), spécialistes agréés en pratique privée (BCS-PP), non-spécialistes dans un hôpital d'enseignement vétérinaire (DVM-VTH) et non-spécialistes en pratique privée (DVM-PP). Les BCS-VTH, les BSC-PP et les DVM-VTH étaient plus à l'aise lors de l'utilisation de l'échelle de Glasgow modifiée (MGCS) que les DVM-PP (P < 0,001, P < 0,001 et P = 0,009, respectivement). Tous les répondants ont choisi les diagnostics suivants le plus fréquemment : valeur d'hématocrite/solides totaux (95,6 %), glycémie (96,7 %) et tension artérielle (95,0 %). Le groupe DVM-VTH a choisi les éléments suivants plus fréquemment que le groupe DVM-PP : tomodensitométrie (19,4 % contre 4,5 %; P = 0,027), gaz du sang veineux ou artériel (83,9 % contre 46,3 %; P < 0,001), électrocardiographie (71,0 % contre 44,8 %; P = 0,018), lactate (87,1 % contre 59,7 %; P = 0,009) et une brève échographie thoracique (87,1 % contre 62,7 %; P = 0,017). Le groupe BCS-PP a choisi la solution saline hypertonique plus fréquemment que le groupe DVM-PP (94,1 % contre 74,6 %; P = 0,005). Le groupe DVM-PP a choisi la thérapie corticostéroïde et une thérapie anti-convulsivante plus fréquemment que le groupe BCS-PP (10,4 % contre 0,0 %; P = 0,019; 73,1 % contre 43,1 %; P = 0,004, respectivement). Cette étude souligne la variabilité dans la gestion des TC canins.(Traduit par Isabelle Vallières).

Superior stimulation of female fecundity by subordinate males provides a mechanism for telegony.

When females mate promiscuously, rival males compete to fertilise the ova. In theory, a male can increase his success at siring offspring by inducing the female to lay more eggs, as well as by producing more competitive sperm. Here we report that the evolutionary consequences of fecundity stimulation extend beyond rival males, by experimentally uncovering effects on offspring. With experiments on the burying beetle Nicrophorus vespilloides, we show that smaller subordinate males are better able to stimulate female fecundity than larger, dominant males. Furthermore dominant males also benefit from the greater fecundity induced by smaller males, and so gain from the female's earlier promiscuity - just as predicted by theory. By inducing females to produce more offspring on a limited resource, smaller males cause each larva to be smaller, even those they do not sire themselves. Fecundity stimulation thus promotes the non-genetic inheritance of offspring body size, and provides a mechanism for telegony.

A sustained change in the supply of parental care causes adaptive evolution of offspring morphology.

Although cooperative social interactions within species are considered an important driver of evolutionary change, few studies have experimentally demonstrated that they cause adaptive evolution. Here we address this problem by studying the burying beetle Nicrophorus vespilloides. In this species, parents and larvae work together to obtain nourishment for larvae from the carrion breeding resource: parents feed larvae and larvae also self-feed. We established experimentally evolving populations in which we varied the assistance that parents provided for their offspring and investigated how offspring evolved in response. We show that in populations where parents predictably supplied more care, larval mandibles evolved to be smaller in relation to larval mass, and larvae were correspondingly less self-sufficient. Previous work has shown that antagonistic social interactions can generate escalating evolutionary arms races. Our study shows that cooperative interactions can yield the opposite evolutionary outcome: when one party invests more, the other evolves to invest less.

Hepcidin detects iron deficiency in Sri Lankan adolescents with a high burden of hemoglobinopathy: A diagnostic test accuracy study.

Anemia affects over 800 million women and children globally. Measurement of hepcidin as an index of iron status shows promise, but its diagnostic performance where hemoglobinopathies are prevalent is unclear. We evaluated the performance of hepcidin as a diagnostic test of iron deficiency in adolescents across Sri Lanka. We selected 2273 samples from a nationally representative cross-sectional study of 7526 secondary schoolchildren across Sri Lanka and analyzed associations between hepcidin and participant characteristics, iron indices, inflammatory markers, and hemoglobinopathy states. We evaluated the diagnostic accuracy of hepcidin as a test for iron deficiency with estimation of the AUCROC , sensitivity/specificity at each hepcidin cutoff, and calculation of the Youden Index to find the optimal threshold. Hepcidin was associated with ferritin, sTfR, and hemoglobin. The AUCROC for hepcidin as a test of iron deficiency was 0.78; hepcidin outperformed Hb and sTfR. The Youden index-predicted cutoff to detect iron deficiency (3.2 ng/mL) was similar to thresholds previously identified to predict iron utilization and identify deficiency in African populations. Neither age, sex, nor α- or ß-thalassemia trait affected diagnostic properties of hepcidin. Hepcidin pre-screening would prevent most iron-replete thalassemia carriers from receiving iron whilst still ensuring most iron deficient children were supplemented. Our data indicate that the physiological relationship between hepcidin and iron status transcends specific populations. Measurement of hepcidin in individuals or populations could establish the need for iron interventions. Am. J. Hematol. 92:196-203, 2017. © 2016 Wiley Periodicals, Inc.

Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia.

Withdrawal of iron from serum (hypoferraemia) is a conserved innate immune antimicrobial strategy that can withhold this critical nutrient from invading pathogens, impairing their growth. Hepcidin (Hamp1) is the master regulator of iron and its expression is induced by inflammation. Mice lacking Hamp1 from birth rapidly accumulate iron and are susceptible to infection by blood-dwelling siderophilic bacteria such as Vibrio vulnificus. In order to study the innate immune role of hepcidin against a background of normal iron status, we developed a transgenic mouse model of tamoxifen-sensitive conditional Hamp1 deletion (termed iHamp1-KO mice). These mice attain adulthood with an iron status indistinguishable from littermate controls. Hamp1 disruption and the consequent decline of serum hepcidin concentrations occurred within hours of a single tamoxifen dose. We found that the TLR ligands LPS and Pam3CSK4 and heat-killed Brucella abortus caused an equivalent induction of inflammation in control and iHamp1-KO mice. Pam3CSK4 and B. abortus only caused a drop in serum iron in control mice, while hypoferraemia due to LPS was evident but substantially blunted in iHamp1-KO mice. Our results characterise a powerful new model of rapidly inducible hepcidin disruption, and demonstrate the critical contribution of hepcidin to the hypoferraemia of inflammation.

Investigating the feasibility and acceptability of a cognitive behavioural suicide prevention therapy for people in acute psychiatric wards (the 'INSITE' trial): study protocol for a randomised controlled trial.

BACKGROUND: Suicide is a major cause of preventable death, and suicidal behaviour is prevalent in acute psychiatric wards. People admitted to acute psychiatric wards often experience repeated episodes of suicidal behaviour, causing great distress and heavy use of NHS services. There is little research investigating effective psychological treatments for suicidal patients in inpatient settings although previous research has found support for psychological therapies which specifically target suicidal behaviour. This paper describes the protocol of a single blind RCT to investigate the acceptability and feasibility of a cognitive behavioural intervention targeting suicidality (CBSP) for suicidal people in acute psychiatric wards. METHODS/DESIGN: A single blind RCT comparing treatment as usual (TAU) to TAU plus Cognitive Behavioural Suicide Prevention (CBSP) therapy (TAU + CBSP). Sixty participants (aged 18-65 years) who are suicidal, or have been within the past 3 months, will be recruited from NHS trusts in the North West of England. Our primary objective is to determine whether CBSP is feasible, acceptable and efficacious when compared to patients who receive TAU alone. Secondary aims are the impact of CBSP on suicidal thinking, behaviours, functioning, quality of life, service use and psychological factors associated with suicide. Assessments take place at baseline, 6 weeks and 6 months (end of treatment). The analysis will report on the feasibility and acceptability of CBSP. Qualitative data from staff and service users will inform feasibility and acceptability data. DISCUSSION: Psychiatric inpatients are a high-risk group and the use of psychological therapies in these settings is rare and requires evaluation. This study is essential to investigate the unique contextual challenges involved in delivering psychological therapy to suicidal inpatients and to identify any necessary modifications required within inpatient settings. The findings will inform a larger, definitive trial. TRIAL REGISTRATION: 15 March 2012, PB-PG-1111-26026, NIHR ISRCTN17890126 .

Dimer formation and conformational flexibility ensure cytoplasmic stability and nuclear accumulation of Elk-1.

The ETS (E26) protein Elk-1 serves as a paradigm for mitogen-responsive transcription factors. It is multiply phosphorylated by mitogen-activated protein kinases (MAPKs), which it recruits into pre-initiation complexes on target gene promoters. However, events preparatory to Elk-1 phosphorylation are less well understood. Here, we identify two novel, functional elements in Elk-1 that determine its stability and nuclear accumulation. One element corresponds to a dimerization interface in the ETS domain and the second is a cryptic degron adjacent to the serum response factor (SRF)-interaction domain that marks dimerization-defective Elk-1 for rapid degradation by the ubiquitin-proteasome system. Dimerization appears to be crucial for Elk-1 stability only in the cytoplasm, as latent Elk-1 accumulates in the nucleus and interacts dynamically with DNA as a monomer. These findings define a novel role for the ETS domain of Elk-1 and demonstrate that nuclear accumulation of Elk-1 involves conformational flexibility prior to its phosphorylation by MAPKs.

Modulation of gene expression and tumor cell growth by redox modification of STAT3.

Reactive oxygen species (ROS) promote tumor cell proliferation and survival by directly modulating growth-regulatory molecules and key transcription factors. The signal transducer and activator of transcription 3 (STAT3) is constitutively active in a variety of tumor cell types, where the effect of ROS on the Janus kinase/STAT pathway has been examined. We report here that STAT3 is directly sensitive to intracellular oxidants. Oxidation of conserved cysteines by peroxide decreased STAT3 binding to consensus serum-inducible elements (SIE) in vitro and in vivo and diminished interleukin (IL)-6-mediated reporter expression. Inhibitory effects produced by cysteine oxidation in STAT3 were negated in redox-insensitive STAT3 mutants. In contrast, ROS had no effect on IL-6-induced STAT3 recruitment to the c-myc P2 promoter. Expression of a redox-insensitive STAT3 in breast carcinoma cells accelerated their proliferation while reducing resistance to oxidative stress. Our results implicate STAT3 in coupling intracellular redox homeostasis to cell proliferation and survival.

Mitogen-induced recruitment of ERK and MSK to SRE promoter complexes by ternary complex factor Elk-1.

Many eukaryotic genes are acutely regulated by extra-cellular signals. The c-fos serum response element (SRE) mediates transcriptional activation in response to mitogens through serum response factor (SRF)-dependent recruitment of Elk-1, a mitogen-activated protein kinase (MAPK)-responsive transcription factor. How subsequent events at SRE promoters stimulate initiation of transcription has yet to be fully resolved. Here we show that extra-cellular signal-regulated kinase (ERK) and mitogen and stress-activated kinase (MSK) are recruited to SRE promoter complexes in vitro and in vivo. Their recruitment in vitro correlates with Elk-1 binding and for ERK the D domain/KIM of Elk-1 is specifically involved. In vivo, recruitment of ERK and MSK is stimulated by mitogens, correlates with histone H3 phosphorylation and is impaired by Elk-1 knockdown. Immunocytochemistry and confocal microscopy reveal that ERK appears to associate to some extent with initiating rather than elongating RNA polymerase II. Taken together, our data add to the body of evidence implying that ERK and related MAPKs may fulfil a generic role at the promoters of acutely regulated genes.