Alternative Wnt Signaling Activates YAP/TAZ.

The transcriptional co-activators YAP and TAZ are key regulators of organ size and tissue homeostasis, and their dysregulation contributes to human cancer. Here, we discover YAP/TAZ as bona fide downstream effectors of the alternative Wnt signaling pathway. Wnt5a/b and Wnt3a induce YAP/TAZ activation independent of canonical Wnt/ß-catenin signaling. Mechanistically, we delineate the "alternative Wnt-YAP/TAZ signaling axis" that consists of Wnt-FZD/ROR-Gα12/13-Rho GTPases-Lats1/2 to promote YAP/TAZ activation and TEAD-mediated transcription. YAP/TAZ mediate the biological functions of alternative Wnt signaling, including gene expression, osteogenic differentiation, cell migration, and antagonism of Wnt/ß-catenin signaling. Together, our work establishes YAP/TAZ as critical mediators of alternative Wnt signaling.

Assessing the safety of physical rehabilitation in critically ill patients: a Delphi study.

BACKGROUND: Physical rehabilitation of critically ill patients is implemented to improve physical outcomes from an intensive care stay. However, before rehabilitation is implemented, a risk assessment is essential, based on robust safety data. To develop this information, a uniform definition of relevant adverse events is required. The assessment of cardiovascular stability is particularly relevant before physical activity as there is uncertainty over when it is safe to start rehabilitation with patients receiving vasoactive drugs. METHODS: A three-stage Delphi study was carried out to (a) define adverse events for a general ICU cohort, and (b) to define which risks should be assessed before physical rehabilitation of patients receiving vasoactive drugs. An international group of intensive care clinicians and clinician researchers took part. Former ICU patients and their family members/carers were involved in generating consensus for the definition of adverse events. Round one was an open round where participants gave their suggestions of what to include. In round two, participants rated their agreements with these suggestions using a five-point Likert scale; a 70% consensus agreement threshold was used. Round three was used to re-rate suggestions that had not reached consensus, whilst viewing anonymous feedback of participant ratings from round two. RESULTS: Twenty-four multi-professional ICU clinicians and clinician researchers from 10 countries across five continents were recruited. Average duration of ICU experience was 18 years (standard deviation 8) and 61% had publications related to ICU rehabilitation. For the adverse event definition, five former ICU patients and one patient relative were recruited. The Delphi process had a 97% response rate. Firstly, 54 adverse events reached consensus; an adverse event tool was created and informed by these events. Secondly, 50 risk factors requiring assessment before physical rehabilitation of patients receiving vasoactive drugs reached consensus. A second tool was created, informed by these suggestions. CONCLUSIONS: The adverse event tool can be used in studies of physical rehabilitation to ensure uniform measurement of safety. The risk assessment tool can be used to inform clinical practise when risk assessing when to start rehabilitation with patients receiving vasoactive drugs. Trial registration This study protocol was retrospectively registered on https://www.researchregistry.com/ (researchregistry2991).

The voice and swallowing profile of adults with laryngotracheal stenosis before and after reconstructive surgery: A prospective, descriptive observational study.

OBJECTIVES: Airway reconstruction for laryngo tracheal stenosis (LTS) improves dyspnoea. There is little evidence relating to impact upon voice and swallowing. We explored voice and swallowing outcomes in adults with LTS before and after reconstructive surgery. DESIGN: Outcome measures were collected pre-reconstructive surgery, two-weeks post-surgery and up to 4-6 months post-surgery. SETTING: Tertiary referral centre. PARTICIPANTS: With ethical approval, twenty consecutive adult (≥18 years) LTS patients undergoing airway reconstruction were prospectively recruited. MAIN OUTCOME MEASURES: These included physiological values (maximum phonation time (MPT) and fundamental frequency; penetration aspiration score, residue score), clinician-reported (GRBAS, functional oral intake score, 100ml Water Swallow Test) and patient-reported outcomes (Voice Handicap Index-10, Reflux Symptoms Index, Eating Assessment Tool, Dysphagia Handicap Index). RESULTS: The observational study identified patient-reported and clinician-reported voice and swallow difficulties pre- and post-surgery; median and interquartile range are reported at each time point: Voice Handicap Index-10 23 (8-31); 20.5 (9-33.5), 24.5 (12.5-29); Dysphagia Handicap Index 9 (0-37); 13 (7-44); 15 (4-34); GRBAS grade 1(1-2); 2 (1-2.5); 2(1-2); 100ml Water Swallow Test volume score 16.7 (11.1-20); 14.3 (12.5-16.7); 16.7 (14.3-20.0); 100ml Water Swallow Test capacity score 16.3 ± 9.0; 11.0 ± 4.1; 12.5 ± 2.6. CONCLUSIONS: We present the first prospective data on voice and swallowing outcomes in adults with LTS before and after reconstructive surgery. The variability of the outcomes was higher than expected but importantly, for many the voice and swallow outcomes were not within normal limits before surgery. The clinical value of the study demonstrates the need for individual assessment and management of LTS patients' voice and swallowing.

Regulation of metabolic health by dietary histidine in mice.

Low-protein (LP) diets are associated with a decreased risk of diabetes in humans, and promote leanness and glycaemic control in both rodents and humans. While the effects of an LP diet on glycaemic control are mediated by reduced levels of the branched-chain amino acids, we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to an LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces the weight gain of young, lean male mice, reducing both adipose and lean mass without altering glucose metabolism, and rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese male mice, increasing insulin sensitivity. This normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. Surprisingly, the effects of histidine restriction do not require the energy balance hormone Fgf21. Histidine restriction that was started in midlife promoted leanness and glucose tolerance in aged males but not females, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in male mice and in humans, and suggest that reducing dietary histidine may be a translatable option for the treatment of obesity. KEY POINTS: Protein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan. Restriction of specific individual essential amino acids can recapitulate the benefits of PR. Reduced histidine promotes leanness and increased energy expenditure in male mice. Reduced histidine does not extend the lifespan of mice when begun in midlife. Dietary levels of histidine are positively associated with body mass index in humans.

Enhanced immunoprecipitation techniques for the identification of RNA-binding protein partners: IGF2BP1 interactions in mammary epithelial cells.

RNA-binding proteins (RBPs) regulate the expression of large cohorts of RNA species to produce programmatic changes in cellular phenotypes. To describe the function of RBPs within a cell, it is key to identify their mRNA-binding partners. This is often done by crosslinking nucleic acids to RBPs, followed by chemical release of the nucleic acid fragments for analysis. However, this methodology is lengthy, which involves complex processing with attendant sample losses, thus large amounts of starting materials and prone to artifacts. To evaluate potential alternative technologies, we tested "exclusion-based" purification of immunoprecipitates (IFAST or SLIDE) and report here that these methods can efficiently, rapidly, and specifically isolate RBP-RNA complexes. The analysis requires less than 1% of the starting material required for techniques that include crosslinking. Depending on the antibody used, 50% to 100% starting protein can be retrieved, facilitating the assay of endogenous levels of RBPs; the isolated ribonucleoproteins are subsequently analyzed using standard techniques, to provide a comprehensive portrait of RBP complexes. Using exclusion-based techniques, we show that the mRNA-binding partners for RBP IGF2BP1 in cultured mammary epithelial cells are enriched in mRNAs important for detoxifying superoxides (specifically glutathione peroxidase [GPX]-1 and GPX-2) and mRNAs encoding mitochondrial proteins. We show that these interactions are functionally significant, as loss of function of IGF2BP1 leads to destabilization of GPX mRNAs and reduces mitochondrial membrane potential and oxygen consumption. We speculate that this underlies a consistent requirement for IGF2BP1 for the expression of clonogenic activity in vitro.

Development of a framework and research impact capture tool for nursing, midwifery, allied health professions, healthcare science, pharmacy and psychology (NMAHPPs).

BACKGROUND: There is an ambitious target to create a UK clinical academic workforce representing 1% of clinicians from nursing, midwifery, the allied health professions, healthcare science, pharmacy and psychology (NMAHPPs). Understanding and recording the impact that clinical academics make across healthcare services is crucial if we are to grow, value and support this highly skilled workforce group. However, it is currently difficult to systematically record, collate and report the impacts associated with NMAHPP research activity. The aims of this project were to i) develop a framework outlining the impacts that were important for key stakeholder groups, and ii) create and pilot a research impact capture tool to record these impacts. METHODS: The framework was developed from the existing literature. It was refined, remodelled and approved by multidisciplinary stakeholder involvement, including patient and public representatives, healthcare managers and research-active clinicians. The framework was converted into a series of questions to create an electronic research impact capture tool, which was also refined through feedback from these stakeholder groups. The impact capture tool was piloted with research-active clinicians across a large NHS Trust and its associated organisations. RESULTS: The impact framework contained eight elements: clinical background, research and service improvement activities, research capacity building, research into practice, patients and service users, research dissemination, economics and research funding, and collaborations. Thirty individuals provided data for the research impact capture tool pilot (55% response rate). Respondents reported a range of positive impacts representing all elements of the framework. Importantly, research-activity appeared to be a key driver for recruitment and retention in the sample population. CONCLUSIONS: The impact capture tool is a feasible method of recording the breadth of impacts associated with NMAHPP research activity. We encourage other organisations to collaboratively use and refine our impact capture tool, with the aim of standardising reporting, and facilitating discussions about research activity within clinical appraisal. Pooling and comparing data will also allow comparison between organisations, and assessment of change over time or after implementation of interventions aimed at supporting and increasing research activity.

'Is there something wrong with your voice?' A qualitative study of the voice concerns of people with laryngotracheal stenosis.

BACKGROUND: Acquired laryngotracheal stenosis (LTS) is a rare condition that causes breathlessness and dyspnoea. Patients have reconstructive airway surgery to improve their breathing difficulties, but both LTS and the surgery can cause voice difficulties. The existing evidence base for management of voice difficulties for adults with LTS focuses on symptoms. There is limited information to provide clinical guidance for speech and language therapists (SLTs) and a limited understanding of the impact of voice changes on adults with LTS. AIM: To investigate the lived experience of adults with laryngotracheal stenosis (LTS), who have had reconstructive surgery; here focussing on voice concerns with the aim of guiding clinical care for SLTs. METHODS AND PROCEDURES: A phenomenological, qualitative study design was used. Focus groups and semi-structured interviews were completed with adults living with LTS who had had reconstructive surgery. Audio recordings were transcribed and inductive thematic analysis was used by the research team to identify themes and sub-themes. OUTCOMES AND RESULTS: A total of 24 participants (five focus groups and two interviews) took part in the study before thematic saturation was identified in analysis. Three main themes were identified specific to the experience of living with LTS: the Medical, Physical and Emotional journey. All participants referenced voice difficulties as they related to each of these overall themes. Sub-themes directly related to voice included experience of surgery, information provision, staff expertise/complacency, symptoms, symptom management, identity, support networks, impact on life and living with a chronic condition. CONCLUSIONS AND IMPLICATIONS: In this qualitative study participants have described the integral part voice difficulties play in their lived experience of LTS and reconstructive surgery. This is considered in the context of their clinical care and the need for individualised management and information provision throughout the course of their condition. The broader research literature relating to voice difficulties is explored with links made to people with LTS and recommendations made for future research into people living with LTS and dysphonia. WHAT THIS PAPER ADDS: What is already known on this subject Adults with laryngotracheal stenosis (LTS) experience voice changes as a result of their condition, and the surgeries necessary as a treatment. These changes can lead to altered pitch, vocal fatigue, loss of pitch range and loss of volume control. Although there are known psychosocial implications both to living with a chronic condition and voice difficulties there has been no research exploring this in adults with LTS, and there is minimal clinical guidance for speech and language therapists (SLTs) working with these patients. What this paper adds to existing knowledge This research is the first study to explore the lived experience of adults with LTS who undergo reconstructive surgery, focusing on their voice concerns. This study demonstrates the multifactorial impacts of voice changes on all aspects of the lives of adults with LTS and the need for individualised information provision and clinical care to help support them. What are the potential or actual clinical implications of this work? Adults with LTS want expert SLTs to facilitate their care and support them throughout their LTS journey alongside other support networks. They want to be carefully prepared for reconstructive surgery and given clear information about symptoms and management of their voice difficulties. This has led to the reorganisation of the care pathway at our centre, and the introduction of a patient-led pretreatment session.

An investigation of the control of quadriceps in people who are hypermobile; a case control design. Do the results impact our choice of exercise for people with symptomatic hypermobility?

BACKGROUND: People with symptomatic hypermobility have altered proprioception however, the origin of this is unclear and needs further investigation to target rehabilitation appropriately. The objective of this investigation was to explore the corticospinal and reflex control of quadriceps and see if it differed between three groups of people: those who have symptomatic hypermobility, asymptomatic hypermobility and normal flexibility. METHODS: Using Transcranial Magnetic Stimulation (TMS) and electrical stimulation of peripheral nerves, motor evoked potentials (MEPs) and Hoffman (H) reflexes of quadriceps were evoked in the three groups of people. The threshold and latency of MEPs and the slope of the input-output curves and the amplitude of MEPs and H reflexes were compared across the groups. RESULTS: The slope of the input-output curve created from MEPs as a result of TMS was steeper in people with symptomatic hypermobility when compared to asymptomatic and normally flexible people (p = 0.04). There were no other differences between the groups. CONCLUSION: Corticospinal excitability and the excitability at the motoneurone pool are not likely candidates for the origin of proprioceptive loss in people with symptomatic hypermobility. This is discussed in the light of other work to suggest the receptor sitting in hypermobile connective tissue is a likely candidate. This suggests that treatment aimed at improving receptor responsiveness through increasing muscle tone, may be an effective rehabilitation strategy.

Not Just Dyspnoea: Swallowing as a Concern for Adults with Laryngotracheal Stenosis Undergoing Airway Reconstruction.

Acquired laryngotracheal stenosis (LTS) is a rare condition causing dyspnea and stridor. Patients often require multiple surgical procedures with no guarantee of a definitive outcome. Difficulty swallowing is a recognised problem associated with LTS and the reconstructive surgeries required to manage the condition. The breathlessness patient's experience impacts on swallowing, and the vulnerable structures of the larynx are implicated during complex surgeries. This leads to dysphagia post-surgery, with some patients experiencing more chronic symptoms depending on the biomechanical impact of the surgery, or a pre-existing dysphagia. Despite this there is limited observational research about the dysphagia associated with LTS, with no exploration of the patient experience. Our aim was to investigate patient experience of living with LTS focussing on dysphagia in order to guide clinical practice. A qualitative study was completed using focus groups and semi-structured interviews with 24 patients who have had reconstructive surgery for LTS. Thematic analysis was used to identify three over-arching themes: The Physical Journey, The Emotional Journey and The Medical Journey. Key sub-themes included the importance of self-management and control, presence of symptoms, benefits of therapy, living with a life-long condition, fear and anxiety, autonomy, medicalisation of normal processes and the dichotomy between staff expertise and complacency. Swallowing was connected to all themes. The results are reviewed with consideration of the wider literature of lived experience particularly in relation to other chronic conditions and those that carry a high symptom burden such as head and neck cancer. Future clinical and research recommendations have been made. Akin to other clinical groups, adults with LTS are keen that management of their swallowing is person-centred and holistic.

What is a clinical academic? Qualitative interviews with healthcare managers, research-active nurses and other research-active healthcare professionals outside medicine.

AIMS AND OBJECTIVES: To explore the concept of "clinical academic" from the perspectives of healthcare managers and research-active healthcare professionals outside medicine. BACKGROUND: Clinical academics are understood to be healthcare professionals who combine clinical and research responsibilities within their role. However, there is no agreed definition for this term either within or across nursing, midwifery and the other healthcare professions outside medicine. DESIGN: Qualitative service evaluation, reported using the COREQ checklist. METHODS: Semi-structured qualitative interviews were conducted with a purposive sample of eight healthcare managers and 12 research-active clinicians within a UK hospital group. Interviews were audio recorded, transcribed verbatim and analysed using the Framework method. RESULTS: Clinical academics were described in four themes. Two themes explored the components of the role and the contribution of these individuals to their profession: combining clinical practice, research and education; and pushing boundaries. The third theme identified the clinical academic label as: a title that doesn't fit. The final theme examined a characteristic mindset of research-active clinicians. There were no clear differences in the perceptions of managers and research-active clinicians. CONCLUSIONS: Clinical academics were perceived as valuable members of their team and were able to push the boundaries to move their profession forward. Some research-active clinicians did not identify with the term "clinical academic" and for some managers and research-active clinicians, the term was viewed as jargonistic. A clear and accepted definition would aid development of clinical academic career pathways and identities. It would also assist in evaluating the impact of these roles. RELEVANCE TO PRACTICE: As clinical academic roles and opportunities are being developed across the professions outside medicine, it is important to have a shared common understanding of "clinical academic" to support the creation of career pathways and curricula, and to enable the evaluation of these roles.

A qualitative systematic review and thematic synthesis exploring the impacts of clinical academic activity by healthcare professionals outside medicine.

BACKGROUND: There are increasing opportunities for healthcare professionals outside medicine to be involved in and lead clinical research. However, there are few roles within these professions that include time for research. In order to develop such roles, and evaluate effective use of this time, the range of impacts of this clinical academic activity need to be valued and understood by healthcare leaders and managers. To date, these impacts have not been comprehensively explored, but are suggested to extend beyond traditional quantitative impact metrics, such as publications, citations and funding awards. METHODS: Ten databases, four grey literature repositories and a naïve web search engine were systematically searched for articles reporting impacts of clinical academic activity by healthcare professionals outside medicine. Specifically, this did not include the direct impacts of the research findings, rather the impacts of the research activity. All stages of the review were performed by a minimum of two reviewers and reported impacts were categorised qualitatively according to a modified VICTOR (making Visible the ImpaCT Of Research) framework. RESULTS: Of the initial 2704 identified articles, 20 were eligible for inclusion. Identified impacts were mapped to seven themes: impacts for patients; impacts for the service provision and workforce; impacts to research profile, culture and capacity; economic impacts; impacts on staff recruitment and retention; impacts to knowledge exchange; and impacts to the clinical academic. CONCLUSIONS: Several overlapping sub-themes were identified across the main themes. These included the challenges and benefits of balancing clinical and academic roles, the creation and implementation of new evidence, and the development of collaborations and networks. These may be key areas for organisations to explore when looking to support and increase academic activity among healthcare professionals outside medicine. The modified VICTOR tool is a useful starting point for individuals and organisations to record the impact of their research activity. Further work is needed to explore standardised methods of capturing research impact that address the full range of impacts identified in this systematic review and are specific to the context of clinical academics outside medicine.

Adaptation of balance reactions following forward perturbations in people with joint hypermobility syndrome.

BACKGROUND: Joint Hypermobility Syndrome (JHS) is a Heritable Disorder of Connective tissue characterised by joint laxity and chronic widespread arthralgia. People with JHS exhibit a range of other symptoms including balance problems. To explore balance further, the objective of this study is to compare responses to forward perturbations between three groups; people who are hypermobile with (JHS) and without symptoms and people with normal flexibility. METHODS: Twenty-one participants with JHS, 23 participants with Generalised Joint Hypermobility (GJH) and 22 participants who have normal flexibility (NF) stood on a platform that performed 6 sequential, sudden forward perturbations (the platform moved to the anterior to the participant). Electromyographic outcomes (EMG) and kinematics for the lower limbs were recorded using a Vicon motion capture system. Within and between group comparisons were made using Kruskal Wallis tests. RESULTS: There were no significant differences between groups in muscle onset latency. At the 1st perturbation the group with JHS had significantly longer time-to-peak amplitude than the NF group in tibialis anterior, vastus medialis, rectus femoris, vastus lateralis, and than the GJH group in the gluteus medius. The JHS group showed significantly higher cumulative joint angle (CA) than the NF group in the hip and knee at the 1st and 2nd and 6th perturbation, and in the ankle at the 2nd perturbation. Participants with JHS had significantly higher CA than the GJH group at the in the hip and knee in the 1st and 2nd perturbation. There were no significant differences in TTR. CONCLUSIONS: The JHS group were able to normalise the timing of their muscular response in relation to control groups. They were less able to normalise joint CA, which may be indicative of impaired balance control and strength, resulting in reduced stability.

Comparing sagittal plane kinematics and kinetics of gait and stair climbing between hypermobile and non-hypermobile people; a cross-sectional study.

BACKGROUND: Joint Hypermobility Syndrome (JHS) presents with a range of symptoms including widespread joint hypermobility and chronic arthralgia. The study objective was to investigate whether impairments in JHS are due to hypermobility or another factor of JHS by identifying impairments in gait and stair-climbing tasks; an activity that is demanding and so may better show differences between the cohorts. METHODS: Sixty-eight adults participated; 23 JHS, 23 Generalised Joint Hypermobility (GJH), and 22 Normal Flexibility (NF). Inclusion criteria for JHS participants were a positive classification using the Brighton Criteria, for GJH a Beighton Score ≥ 4, and for NF a Beighton Score < 4 with no hypermobile knees. Participants were recorded with a 10-camera Vicon system whilst they performed gait and stair-climbing. Temporal-spatial, and sagittal plane kinematic and kinetic outcome measures were calculated and input to statistical analyses by statistical parametric mapping (SPM). RESULTS: During the gait activity JHS had significantly greater stride time and significantly lower velocity than NF, and significantly greater stride time, lower velocity, and lower stride length than GJH. SPM analysis showed no significant differences between groups in gait kinematics. There were significant differences between groups for gait moments and powers; people with JHS tended to have lower moments and generate less power at the ankle, and favour power generation at the knee. A similar strategy was present in stair ascent. During stair descent people with JHS showed significantly more hip flexion than people with NF. CONCLUSIONS: As there was only one significant difference between GJH and NF we conclude that impairments cannot be attributed to hypermobility alone, but rather other factor(s) of JHS. The results show that both gait and stair-climbing is impaired in JHS. Stair-climbing results indicate that JHS are using a knee-strategy and avoiding use of the ankle, which may be a factor for clinicians to consider during treatment.

Prolonged standing behaviour in people with joint hypermobility syndrome.

BACKGROUND: Joint Hypermobility Syndrome (JHS) is a rare Heritable Disorder of Connective tissue characterised by generalised joint laxity and chronic widespread pain. Joint Hypermobility Syndrome has a large impact on patients' day to day activities, and many complain of symptoms when standing for prolonged periods. This study investigates whether people with JHS exhibit the same behaviours to deal with the effects of prolonged standing as people with equal hypermobility and no pain, and people with normal flexibility and no pain. METHODS: Twenty three people with JHS, 22 people with Generalised Joint Hypermobility (GJH), and 22 people with normal flexibility (NF) were asked to stand for a maximum of 15 min across two force-plates. Fidgets were counted and quantified using a cumulative sum algorithm and sway parameters of the quiet standing periods between fidgets were calculated. RESULTS: Average standing time for participants with JHS was 7.35 min and none stood for the full 15 min. All participants with GJH and NF completed 15 min of standing. There were no differences in fidgeting behaviour between any groups. There was a difference in anteroposterior sway (p = .029) during the quiet standing periods. CONCLUSION: There is no evidence to suggest people with JHS exhibit different fidgeting behaviour. Increased anteroposterior-sway may suggest a muscle weakness and strengthening muscles around the ankle may reduce postural sway and potentially improve the ability to stand for prolonged periods.

The association of sensory phenotype and concomitant mood, sleep and functional impairment with the outcome of carpal tunnel surgery.

BACKGROUND: Up to 25% of people who have had carpal tunnel release surgery (CTR) fail to report improvement; however, evidence for prognostic indicators in this surgical cohort is limited. To identify candidate prognostic factors, this study investigated the association of quantitative sensory testing (QST) derived sensory phenotype and attendant impairment with patient-reported surgical outcome. METHODS: With ethical approval and informed consent, this prospective observational longitudinal study recruited patients from two London hospitals. Multimodal phenotyping measures including quantitative sensory testing (QST), pain parameters, insomnia, pain-related worry, mood and function, were evaluated prior to; and at 3- and 6-months post-surgery. Pain in median nerve distribution with electrophysiologically confirmed conduction delay and DN4 score ≥ 4 was defined as neuropathic. Primary outcome was patient-rated change at 6 months, dichotomised as poor outcome; "worse" or "no change" and good outcome; "slightly better", "much better" or "completely cured". RESULTS: Seventy-six patients participated. Prior to surgery, substantial heterogeneity in established categories of somatosensory function was observed with 21% of participants categorised as having a healthy sensory phenotype; 29% with thermal hyperalgesia; 32% mechanical hyperalgesia and 18% sensory loss. Seventy six percent of participants were classified as having neuropathic pain, 33% with high levels of pain related worry and 64% with clinical insomnia. Observed differences in pain, sleep impairment, psychological factors and function, between sensory phenotypic groups, was not significant. At 3- and 6-months post-surgery there was significant improvement in all phenotyping measures with a moderate to large effect size. Thermal and mechanical measures of somatosensation improved (p < 0.001), as did functional ability (p < 0.001). Symptom severity diminished (p < 0.001), as did pain-related worry (p < 0.001), anxiety (p = 0.02) and insomnia (p < 0.001). Patient-rated surgical outcome was good in 92% of the cohort, poor in 8%. Baseline sensory phenotype category was not associated with surgical outcome however pain-related worry, anxiety and functional interference were significantly associated with outcome (p ≤ 0.05). CONCLUSION: In patients undergoing carpal tunnel surgery, pain-related worry, anxiety and pain functional interference are candidate prognostic outcome factors and require further elucidation.

Are People With Joint Hypermobility Syndrome Slow to Strengthen?

OBJECTIVES: To investigate whether the rate of change of muscle strength in people with joint hypermobility syndrome (JHS) who have anterior knee pain (AKP) differs when compared to 2 control groups who have AKP and to evaluate the relationship between strength and pain as well as the effect of strength upon activity and knee function. DESIGN: A cohort study, with 3 groups: JHS with AKP, generalized joint hypermobility with AKP (GJH), and normal flexibility with AKP (control group [CG]). Follow-up appointments were performed every 2 weeks for 16 weeks. SETTING: The physiotherapy outpatient department within a London (United Kingdom) hospital. PARTICIPANTS: A total of 102 people, aged between 18 and 55 years, were recruited between July 2014 and March 2016; 47 JHS, 29 GJH, and 26 CG (N=102). After 16 weeks, 31, 20, and 21 participants completed the study, respectively. Participants were recruited from support groups, a London hospital group and university, local sports centers, and clubs. INTERVENTIONS: Individualized leg exercises for 16 weeks. MAIN OUTCOME MEASURE: Muscle torque generated from the lower limb, every 2 weeks for 16 weeks. RESULTS: There was no difference in the rate of change of concentric muscle strength between the JHS group and the CG or GJH group (P>.88 and P>.97). There was no difference in the rate of change of eccentric muscle strength between the JHS group and the CG or GJH group (P>.60 and P>.94). However, people with JHS were significantly weaker than the other 2 groups, taking 3 to 4 months to reach the baseline strength of the GJH group. CONCLUSION: People with JHS can strengthen at the same rate as other people in pain.

Restoration of metabolic health by decreased consumption of branched-chain amino acids.

KEY POINTS: We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain. In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice. Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high-fat, high-sugar diet. A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure. We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets. ABSTRACT: Obesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched-chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin-resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet-induced obese mice with pre-existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet-induced obesity and improves glucoregulatory control in diet-induced obese mice. Most dramatically, mice eating an otherwise unhealthy high-calorie, high-sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance.

Syndecan-1 is required to maintain intradermal fat and prevent cold stress.

Homeostatic temperature regulation is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and nervous regulators. Here, we report that loss of the heparan sulfate proteoglycan, syndecan-1, causes a profoundly depleted intradermal fat layer, which provides crucial thermogenic insulation for mammals. Mice without syndecan-1 enter torpor upon fasting and show multiple indicators of cold stress, including activation of the stress checkpoint p38α in brown adipose tissue, liver and lung. The metabolic phenotype in mutant mice, including reduced liver glycogen, is rescued by housing at thermoneutrality, suggesting that reduced insulation in cool temperatures underlies the observed phenotypes. We find that syndecan-1, which functions as a facultative lipoprotein uptake receptor, is required for adipocyte differentiation in vitro. Intradermal fat shows highly dynamic differentiation, continuously expanding and involuting in response to hair cycle and ambient temperature. This physiology probably confers a unique role for Sdc1 in this adipocyte sub-type. The PPARγ agonist rosiglitazone rescues Sdc1-/- intradermal adipose tissue, placing PPARγ downstream of Sdc1 in triggering adipocyte differentiation. Our study indicates that disruption of intradermal adipose tissue development results in cold stress and complex metabolic pathology.

Two Isoforms of the RNA Binding Protein, Coding Region Determinant-binding Protein (CRD-BP/IGF2BP1), Are Expressed in Breast Epithelium and Support Clonogenic Growth of Breast Tumor Cells.

CRD-BP/IGF2BP1 has been characterized as an "oncofetal" RNA binding protein typically highly expressed in embryonic tissues, suppressed in normal adult tissues, but induced in many tumor types. In this study, we show that adult breast tissues express ubiquitous but low levels of CRD-BP protein and mRNA. Although CRD-BP mRNA expression is induced in breast tumor cells, levels remain ∼1000-fold lower than in embryonic tissues. Despite low expression levels, CRD-BP is required for clonogenic growth of breast cancer cells. We reveal that because the most common protein isoform in normal adult breast and breast tumors has an N-terminal deletion (lacking two RNA recognition motif (RRM) domains) and is therefore missing antibody epitopes, CRD-BP expression has been under-reported by previous studies. We show that a CRD-BP mutant mouse strain retains expression of the shorter transcript (ΔN-CRD-BP), which originates in intron 2, suggesting that the impact of complete ablation of this gene in mice is not yet known. Either the full-length CRD-BP or the N-terminally truncated version can rescue the clonogenicity of CRD-BP knockdown breast cancer cells, suggesting that clonogenic function is served by either CRD-BP isoform. In summary, although CRD-BP expression levels are low in breast cancer cells, this protein is necessary for clonogenic activity.

WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines.

BACKGROUND: Invasive lobular carcinoma (ILC) of the breast typically presents with clinical biomarkers consistent with a favorable response to endocrine therapies, and over 90 % of ILC cases express the estrogen receptor (ER). However, a subset of ILC cases may be resistant to endocrine therapies, suggesting that ER biology is unique in ILC. Using ILC cell lines, we previously demonstrated that ER regulates a distinct gene expression program in ILC cells, and we hypothesized that these ER-driven pathways modulate the endocrine response in ILC. One potential novel pathway is via the Wnt ligand WNT4, a critical signaling molecule in mammary gland development regulated by the progesterone receptor. METHODS: The ILC cell lines MDA-MB-134-VI, SUM44PE, and BCK4 were used to assess WNT4 gene expression and regulation, as well as the role of WNT4 in estrogen-regulated proliferation. To assess these mechanisms in the context of endocrine resistance, we developed novel ILC endocrine-resistant long-term estrogen-deprived (ILC-LTED) models. ILC and ILC-LTED cell lines were used to identify upstream regulators and downstream signaling effectors of WNT4 signaling. RESULTS: ILC cells co-opted WNT4 signaling by placing it under direct ER control. We observed that ER regulation of WNT4 correlated with use of an ER binding site at the WNT4 locus, specifically in ILC cells. Further, WNT4 was required for endocrine response in ILC cells, as WNT4 knockdown blocked estrogen-induced proliferation. ILC-LTED cells remained dependent on WNT4 for proliferation, by either maintaining ER function and WNT4 regulation or uncoupling WNT4 from ER and upregulating WNT4 expression. In the latter case, WNT4 expression was driven by activated nuclear factor kappa-B signaling in ILC-LTED cells. In ILC and ILC-LTED cells, WNT4 led to suppression of CDKN1A/p21, which is critical for ILC cell proliferation. CDKN1A knockdown partially reversed the effects of WNT4 knockdown. CONCLUSIONS: WNT4 drives a novel signaling pathway in ILC cells, with a critical role in estrogen-induced growth that may also mediate endocrine resistance. WNT4 signaling may represent a novel target to modulate endocrine response specifically for patients with ILC.