A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response.

Liver fibrosis is a reversible wound-healing response involving TGFß1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFß1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFß1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFß1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis.

Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner.

Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non-immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS-dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil-induced senescence may be beneficial during aging and age-related disease.

Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis.

Age-related chronic inflammation promotes cellular senescence, chronic disease, cancer, and reduced lifespan. In this study, we wanted to explore the effects of a moderate exercise regimen on inflammatory liver disease and tumorigenesis. We used an established model of spontaneous inflammaging, steatosis, and cancer (nfkb1-/- mouse) to demonstrate whether 3 mo of moderate aerobic exercise was sufficient to suppress liver disease and cancer development. Interventional exercise when applied at a relatively late disease stage was effective at reducing tissue inflammation (liver, lung, and stomach), oxidative damage, and cellular senescence, and it reversed hepatic steatosis and prevented tumor development. Underlying these benefits were transcriptional changes in enzymes driving the conversion of tryptophan to NAD+, this leading to increased hepatic NAD+ and elevated activity of the NAD+-dependent deacetylase sirtuin. Increased SIRT activity was correlated with enhanced deacetylation of key transcriptional regulators of inflammation and metabolism, NF-κB (p65), and PGC-1α. We propose that moderate exercise can effectively reprogram pre-established inflammatory and metabolic pathologies in aging with the benefit of prevention of disease.

Compounds enhancing human sperm motility identified using a high-throughput phenotypic screening platform.

STUDY QUESTION: Can a high-throughput screening (HTS) platform facilitate male fertility drug discovery? SUMMARY ANSWER: An HTS platform identified a large number of compounds that enhanced sperm motility. WHAT IS KNOWN ALREADY: Several efforts to find small molecules modulating sperm function have been performed but none have used high-throughput technology. STUDY DESIGN, SIZE, DURATION: Healthy donor semen samples were used and samples were pooled (3-5 donors per pool). Primary screening was performed singly; dose-response screening was performed in duplicate (using independent donor pools). PARTICIPANTS/MATERIALS, SETTING, METHODS: Spermatozoa isolated from healthy donors were prepared by density gradient centrifugation and incubated in 384-well plates with compounds (6.25 µM) to identify those compounds with enhancing effects on motility. Approximately 17 000 compounds from the libraries, ReFRAME, Prestwick, Tocris, LOPAC, CLOUD and MMV Pathogen Box, were screened. Dose-response experiments of screening hits were performed to confirm the enhancing effect on sperm motility. Experiments were performed in a university setting. MAIN RESULTS AND THE ROLE OF CHANCE: From our primary single concentration screening, 105 compounds elicited an enhancing effect on sperm motility compared to dimethylsulphoxide-treated wells. Confirmed enhancing compounds were grouped based on their annotated targets/target classes. A major target class, phosphodiesterase inhibitors, were identified, in particular PDE10A inhibitors as well as number of compounds not previously known to enhance human sperm motility, such as those related to GABA signalling. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Although this approach provides data about the activity of the compound, it is only a starting point. For example, further substantive experiments are necessary to provide a more comprehensive picture of each compound's activity, the effect on the kinetics of the cell populations and subpopulations, and their potential mechanisms of action. Compounds have been tested with prepared donor spermatozoa, incubated under non-capacitating conditions, and only incubated with compounds for a relatively short period of time. Therefore, the effect of compounds under different conditions, for example in whole semen, for longer incubation times, or using samples from patient groups, may be different and require further study. All experiments were performed in vitro. WIDER IMPLICATIONS OF THE FINDINGS: This phenotypic screening assay identified a large number of compounds that increased sperm motility. In addition to furthering our understanding of human sperm function, for example identifying new avenues for discovery, we highlight potential compounds as promising start-point for a medicinal chemistry programme for potential enhancement of male fertility. Moreover, with disclosure of the results of screening, we present a substantial resource to inform further work in the field. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Bill and Melinda Gates Foundation, Scottish Funding Council and Scottish Universities Life Science Alliance. C.L.R.B. is Editor for RBMO. C.L.R.B. receives funding from Chief Scientists Office (Scotland), ESHRE and Genus PLC, consulting fees from Exscientia and lecture fees from Cooper Surgical and Ferring. S.M.d.S. is an Associate Editor of Human Reproduction, and an Associate Editor of Reproduction and Fertility. S.M.d.S. receives funding from Cooper Surgical and British Dietetic Society. No other authors declared a COI.

Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs.

Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer's disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including 'epileptic-like' seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD.

Feasibility and safety of radical prostatectomy for oligo-metastatic prostate cancer: the Testing Radical prostatectomy in men with prostate cancer and oligo-Metastases to the bone (TRoMbone) trial.

OBJECTIVES: To test the feasibility of randomisation to radical prostatectomy (RP) plus pelvic lymphadenectomy in addition to standard-of-care (SOC) systemic therapy in men with newly diagnosed oligo-metastatic prostate cancer. PATIENTS AND METHODS: A prospective, randomised, non-blinded, feasibility clinical trial with an embedded QuinteT Recruitment Intervention (QRI) to optimise recruitment was conducted in nine nationwide tertiary care centres undertaking high-volume robotic surgery. We aimed to randomise 50 men with synchronous oligo-metastatic prostate cancer within an 18-month recruitment period to SOC systemic therapy vs SOC plus RP (intervention arm). The main outcome measures were: ability to randomise patients, optimised by a QRI; EuroQoL five Dimensions five Levels (EQ-5D-5L) questionnaires to capture quality-of-life (QoL) data at baseline and 3 months post-randomisation; routine clinicopathological assessment to capture adverse events and prostate-specific antigen in both arms, plus standard perioperative parameters in the surgical arm. RESULTS: A total of 51 men were randomised within 14 months (one was subsequently deemed ineligible), with 60-83% accrual rate in centres that recruited at least two patients. All patients completed the trial follow-up; one patient in the intervention arm subsequently did not undergo the surgical intervention and one in the SOC arm refused all therapies. The QRI positively impacted recruitment. QoL data showed similarly high functioning in both study arms. Surgery for men with oligo-metastatic prostate cancer was found to be safe and had similar impact on early functional outcomes as surgery for standard indication. CONCLUSION: It is feasible to randomise men with synchronous oligo-metastatic prostate cancer to a surgical intervention in addition to standard systemic therapies. While surgery appeared safe with no substantial impact on QoL in this feasibility study, a large randomised controlled trial is now warranted to examine treatment effectiveness of this additional component in the multimodality management of oligo-metastatic prostate cancer.

Applications of 3-dimensional printing in small-animal surgery: A review of current practices.

Three-dimensional (3D) printing, also called rapid prototyping or additive manufacturing, transforms digital images into 3D printed objects, typically by layering consecutive thin films of material. This technology has become increasingly accessible to the public, prompting applications in veterinary surgery. Three-dimensional prints provide direct visualization of complex 3D structures and also haptic feedback relevant to surgery. The main objective of this review is to report current applications of 3D printing in small-animal surgery, including surgical education, preoperative planning, and treatment of tissue defects. The reported uses of 3D prints, their proposed advantages, and current limitations are discussed considering published evidence. Aspects of the manufacturing process specific to each application are described, along with current practices in veterinary surgery.

Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial.

BACKGROUND: Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs. METHODS: We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2-T4 pN0-N3 M0 or pTany N1-3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants. FINDINGS: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30-0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0-47·5). 3-year event-free estimates were 71% (95% CI 61-78) and 46% (36-56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported. INTERPRETATION: Gemcitabine-platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population. FUNDING: Cancer Research UK.

CDK4/6 inhibitors in breast cancer - from in vitro models to clinical trials.

Background: Breast cancer (BC) is one of the leading causes of cancer-related deaths worldwide. Standard therapies aim to disrupt pathways that regulate the growth and survival of BC cells. Therapeutic agents such as endocrine therapy target hormone dependent cancer cells and have shown to be suitable approaches in BC treatment. However, in the case of metastatic BC, curative options are limited, thus strategies have been explored to improve survival and clinical benefit. In this review we provide an up to date overview of the development of anti-cancer agents, particularly the newly developed CDK4/6 inhibitors.Material and methods: A search of PubMed was conducted to identify preclinical data surrounding the development of endocrine therapy and CDK4/6 inhibitors in early and metastatic BC. Clinical data were also sought using PubMed and clinicaltrials.gov.Results: Agents targeting oestrogen and its receptor have demonstrated positive outcomes in clinical trial with improvements in objective responses and overall survival. However, patients do exhibit adverse effects and some will eventually fail to respond to endocrine therapy. Subsequently, the development and success of 3rd generation CDK4/6 inhibitors in preclinical studies has allowed their introduction in clinical studies. In patients with ER + BC, CDK4/6 have demonstrated dramatic improvements in progression free survival when used in combination with endocrine therapies. Similar findings were also observed in metastatic disease. Adverse effects were limited in CDK4/6 treated patients, demonstrating the safety of these agents.Conclusion: CDK4/6 inhibitors are highly specific making them a safe and viable therapeutic for BC and there is increasing evidence of their potential to improve survival, even in the metastatic setting. Although a number of trials have demonstrated this, as a lone therapy or in combination, optimisation of treatment scheduling are still required in further clinical investigations.

Investigating fractal dimension, heart rate variability, and memory during different image sequencing regimes in young adults.

The goal of this study is to investigate patterns that emerge in brain and heart signals in response to external stimulating image regimes. Data were collected from 84 subjects of ages 18-22. Subjects viewed a series of both neutrally and negatively arousing pictures during 2-min and 18-s-long segments repeated nine times. Both brain [electroencephalogram (EEG)] and heart signals [electrocardiogram (EKG)] were recorded for the duration of the study (ranging from 1.5 to 2.5 h) and analyzed using nonlinear techniques. Specifically, the fractal dimension was computed from the EEG to determine how this voltage trace is related to the image sequencing. Our results showed that subjects visually stimulated by a series of mixed images (a randomized set of neutrally or negatively arousing images) had a significantly higher fractal dimension compared to subjects visually triggered by pure images (an organized set of either all neutral or all negatively arousing images). In addition, our results showed that subjects who performed better on memory recall had a higher fractal dimension computed from the EEG. Analysis of EKG also showed greater heart rate variability in subjects who viewed a series of mixed images compared to subjects visually triggered by pure images. Overall, our results show that the healthy brain and heart are responsive to environmental stimuli that promote adaptability, flexibility, and agility.

Cold reacting anti-M causing delayed hemolytic disease of the newborn.

BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) is due to passively transferred maternal antibodies directed against fetal red blood cell (RBC) antigens and can lead to severe morbidity and mortality. Anti-M is usually a naturally occurring antibody of low clinical significance, although occasionally severe cases of HDFN are seen. CASE REPORTS: Two M+ sisters are presented, each developing hemolysis during the first 2 weeks of life due to maternal anti-M, resulting in severe anemia and requiring blood transfusion. RBC agglutination was observed in peripheral blood samples of both infants at room temperature with dissociation at 37°C. Maternal anti-M detected by column indirect agglutination technique, was of low titer (1:16) and demonstrated low thermal amplitude, reacting in saline at 4°C but was not detectable in saline at 37°C. CONCLUSIONS: Anti-M of low thermal amplitude may cause hemolytic disease of the newborn with laboratory features resembling cold agglutinin disease.

Novel Use of Porcine Urinary Bladder Matrix in the Exenterated Socket.

The aim of exenteration reconstruction is to stabilize the postsurgical wound bed to promote expeditious healing particularly in patients who are undergoing adjuvant radiation and/or chemotherapy. Porcine urinary bladder matrix has previously been used successfully as a wound-healing scaffold in treatment of burns and in acute, chronic, and surgical wounds, but the use of these products has not previously been reported in the exenterated orbit. The authors present a case of the novel use of porcine urinary bladder matrix in a pediatric patient who underwent exenteration for recurrent embryonal rhabdomyosarcoma, subsequent split-thickness skin grafting, and adjuvant radiation.

Neutrophils: driving progression and poor prognosis in hepatocellular carcinoma?

BACKGROUND: Irrespective of the underlying aetiology, 90% of hepatocellular carcinomas arise and progress on a background of chronic inflammation. We have explored the independent prognostic value of circulating inflammatory cells. METHODS: Peripheral blood count data sets from 583 consecutive patients presenting to a single UK centre (2000-2010) were analysed for associations with tumour stage, liver function, performance status (PST) and survival. Validation was in an independent Hong Kong cohort (585 patients; 2007-2013). RESULTS: In both UK and Hong Kong cohorts, neutrophils, platelets, lymphocytes, the neutrophil/lymphocyte ratio (NLR) and the Systemic Immune-Inflammation Index (SII) correlated stepwise, either increasing or decreasing (lymphocytes), with tumour node metastasis (TNM) and Childs-Pugh stage, PST and consequently with the combined Barcelona Clinic for Liver Cancer stage. Survival analyses confirmed the NLR and SII as highly significant prognostic biomarkers. Focused on individual cell types, only the neutrophil count was independently associated with both TNM stage and PST, as well as being significantly and independently associated with poorer survival. CONCLUSIONS: In this study of 1168 patients, neutrophils alone, rather than lymphocytes or platelets, were independently associated with outcome. These data support further characterisation of a potentially distinctive role for neutrophils as facilitators of tumour progression and deteriorating performance.

Ambiguous loss and post-traumatic growth: Experiences of mothers whose school-aged children were born extremely prematurely.

AIMS AND OBJECTIVES: To develop insight into the experiences of mothers whose school-aged children were born extremely prematurely. BACKGROUND: Extreme prematurity, where infants are born at 28 weeks or earlier, has significant initial maternal impact in terms of distress, uncertainty and disruption to maternal identity. However, little is known about the experiences of these mothers beyond their child's infancy. DESIGN: A qualitative study was undertaken using thematic analysis, drawing on a cluster of social constructionist theories that have been applied to studies investigating mothers' early preterm or childhood disability experiences. METHODS: The study involved face-to-face interviews with nine mothers whose children were born prior to 28 weeks and were now aged between 4-to-7 years old. RESULTS: Participants described a prolonged period of anxiety, and relative isolation due to infection fears and complex care regimes. Although they grieved their different mothering trajectory, they celebrated their children's successes and noted their own resilience. The following themes were identified: traumatic beginnings; dialectics and the horror-miracle contradiction; labour-intensive parenting and managing the multidisciplinary team; stigma and storying the meaning of premature birth; and impact on relationships. CONCLUSIONS: Women's vulnerability and resilience are evident long after the birth of an extremely prematurely born infant. Women value connection with similar mothers, and yet finding community is often daunting due to their children's early complex needs. Generalist healthcare providers may be unaware of the experiences these mothers have endured, and need to enquire about their well-being. RELEVANCE TO CLINICAL PRACTICE: The lives of mothers of extremely preterm infants may take years to merge with the world of those mothers who parent healthy, term infants. Neonatal nurses and those in primary health care are well placed to notice signs of isolation, depression and anxiety, and to support and refer women appropriately.

Workflow standardization of a novel team care model to improve chronic care: a quasi-experimental study.

BACKGROUND: Team-based chronic care models have not been widely adopted in community settings, partly due to their varying effectiveness in randomized control trials, implementation challenges, and concerns about physician acceptance. The Palo Alto Medical Foundation designed and implemented "Champion," a novel team-based model that includes new standard work (e.g. proactive patient outreach, pre-visit schedule grooming, depression screening, care planning, health coaching) to support patients' self-management of hypertension and diabetes. We investigated whether Champion improved clinical outcomes. METHODS: We conducted a quasi-experimental study comparing the Champion clinic-level intervention (n = 38 physicians) with a usual care clinic (n = 37 physicians) in Northern California. The primary outcomes, blood pressure and glycohemoglobin (A1c), were analyzed using a piecewise linear growth curve model for patients exposed to a Champion physician visit (n = 3156) or usual care visit (n = 8034) in the two years prior and one year post implementation. Secondary outcomes were provider experience, compared at baseline and 12 months in both the intervention and usual care clinics using multi-level ordered logistic modeling, and electronic health record based fidelity measures. RESULTS: Compared to usual care, in the first 6 months after a Champion physician visit, diabetes patients aged 18-75 experienced an additional -1.13 mm Hg (95% CI: -2.23 to -0.04) decline in diastolic blood pressure and -0.47 (95% CI: -0.61 to -0.33) decline in A1c. There were no additional improvements in blood pressure or A1c 6 to 12 months post physician visit. At 12 months, Champion physicians reported improved experience with managing chronic care patients in 6 of 7 survey items (p < 0.05), but compared to usual, this difference was only statistically significant for one item (p < 0.05). Fidelity to standard work was uneven; depression screening was the most commonly documented element (85% of patients), while care plans were the least (30.8% of patients). CONCLUSIONS: Champion standard work improved glycemic control over the first 6 months and physicians' experience with managing chronic care; changes in blood pressure were not clinically meaningful. Our results suggest the need to understand the relationship between the intervention, the contextual features of implementation, and fidelity to further improve chronic disease outcomes. This study was retrospectively registered with the ISRCTN Registry on March 15, 2017 (ISRCTN11341906).

A prospective audit of pain profiles following general and urological surgery in children.

BACKGROUND: Postoperative pain is frequently undertreated in children both in hospital and at home following discharge. Pain has both short- and long-term consequences for children, their families, and the healthcare system. A greater understanding of procedure-specific postoperative pain trajectories is required to improve pain management. AIM: To determine the duration and severity of acute postoperative pain experienced by children undergoing 8 different general and urological procedures (primary outcomes). Behavioral disturbance rates, nausea and vomiting scores, and parental satisfaction were also examined during the follow-up period (secondary outcomes). METHOD: Families of children (0-18 years) undergoing common general and urological procedures were invited to enroll in the study. Children's pain scores, measured using a parental proxy 0-10 numerical rating scale, were collected by telephone interview until pain was resolved. Analgesia prescribed and given, behavioral disturbance, nausea and vomiting scores, the method of medication education communication, and parental satisfaction were also measured. RESULTS: Of 360 patients recruited, 326 complete datasets were available. Patients underwent laparoscopic appendicectomy (57), open appendicectomy (19), circumcision (50), cystoscopy (52), hypospadias repair (22), inguinal hernia repair (51), orchidopexy (51), or umbilical hernia repair (24). Postoperative pain peaked on the day of or the day after surgery in all groups, and decreased over time. Pain lasted a median duration of 5 postoperative days following open appendicectomy, and 0-2 postoperative days for other procedures. Behavioral disturbance rates closely followed pain scores. Analgesia administration at home varied widely between and within groups. CONCLUSION: Pain management was inadequate in most of the groups studied, particularly after appendicectomy or umbilical hernia repair, with most children experiencing at least moderate pain on the day of and day after surgery. There was a need for a standardized management, with increased dual analgesia prescribing, to ensure that children receive adequate postoperative analgesia in hospital and at home.

Rhythmic auditory cortex activity at multiple timescales shapes stimulus-response gain and background firing.

The phase of low-frequency network activity in the auditory cortex captures changes in neural excitability, entrains to the temporal structure of natural sounds, and correlates with the perceptual performance in acoustic tasks. Although these observations suggest a causal link between network rhythms and perception, it remains unknown how precisely they affect the processes by which neural populations encode sounds. We addressed this question by analyzing neural responses in the auditory cortex of anesthetized rats using stimulus-response models. These models included a parametric dependence on the phase of local field potential rhythms in both stimulus-unrelated background activity and the stimulus-response transfer function. We found that phase-dependent models better reproduced the observed responses than static models, during both stimulation with a series of natural sounds and epochs of silence. This was attributable to two factors: (1) phase-dependent variations in background firing (most prominent for delta; 1-4 Hz); and (2) modulations of response gain that rhythmically amplify and attenuate the responses at specific phases of the rhythm (prominent for frequencies between 2 and 12 Hz). These results provide a quantitative characterization of how slow auditory cortical rhythms shape sound encoding and suggest a differential contribution of network activity at different timescales. In addition, they highlight a putative mechanism that may implement the selective amplification of appropriately timed sound tokens relative to the phase of rhythmic auditory cortex activity.

Conveying Equipoise during Recruitment for Clinical Trials: Qualitative Synthesis of Clinicians' Practices across Six Randomised Controlled Trials.

BACKGROUND: Randomised controlled trials (RCTs) are essential for evidence-based medicine and increasingly rely on front-line clinicians to recruit eligible patients. Clinicians' difficulties with negotiating equipoise is assumed to undermine recruitment, although these issues have not yet been empirically investigated in the context of observable events. We aimed to investigate how clinicians conveyed equipoise during RCT recruitment appointments across six RCTs, with a view to (i) identifying practices that supported or hindered equipoise communication and (ii) exploring how clinicians' reported intentions compared with their actual practices. METHODS AND FINDINGS: Six pragmatic UK-based RCTs were purposefully selected to include several clinical specialties (e.g., oncology, surgery) and types of treatment comparison. The RCTs were all based in secondary-care hospitals (n = 16) around the UK. Clinicians recruiting to the RCTs were interviewed (n = 23) to understand their individual sense of equipoise about the RCT treatments and their intentions for communicating equipoise to patients. Appointments in which these clinicians presented the RCT to trial-eligible patients were audio-recorded (n = 105). The appointments were analysed using thematic and content analysis approaches to identify practices that supported or challenged equipoise communication. A sample of appointments was independently coded by three researchers to optimise reliability in reported findings. Clinicians and patients provided full written consent to be interviewed and have appointments audio-recorded. Interviews revealed that clinicians' sense of equipoise varied: although all were uncertain about which trial treatment was optimal, they expressed different levels of uncertainty, ranging from complete ambivalence to clear beliefs that one treatment was superior. Irrespective of their personal views, all clinicians intended to set their personal biases aside to convey trial treatments neutrally to patients (in accordance with existing evidence). However, equipoise was omitted or compromised in 48/105 (46%) of the recorded appointments. Three commonly recurring practices compromised equipoise communication across the RCTs, irrespective of clinical context. First, equipoise was overridden by clinicians offering treatment recommendations when patients appeared unsure how to proceed or when they asked for the clinician's expert advice. Second, clinicians contradicted equipoise by presenting imbalanced descriptions of trial treatments that conflicted with scientific information stated in the RCT protocols. Third, equipoise was undermined by clinicians disclosing their personal opinions or predictions about trial outcomes, based on their intuition and experience. These broad practices were particularly demonstrated by clinicians who had indicated in interviews that they held less balanced views about trial treatments. A limitation of the study was that clinicians volunteering to take part in the research might have had a particular interest in improving their communication skills. However, the frequency of occurrence of equipoise issues across the RCTs suggests that the findings are likely to be reflective of clinical recruiters' practices more widely. CONCLUSIONS: Communicating equipoise is a challenging process that is easily disrupted. Clinicians' personal views about trial treatments encroached on their ability to convey equipoise to patients. Clinicians should be encouraged to reflect on personal biases and be mindful of the common ways in which these can arise in their discussions with patients. Common pitfalls that recurred irrespective of RCT context indicate opportunities for specific training in communication skills that would be broadly applicable to a wide clinical audience.

Pain after discharge following head and neck surgery in children.

BACKGROUND: It is well established that children experience significant pain for a considerable period following adenotonsillectomy. Less is known, however, about pain following other common head and neck operations. AIM: The aim of this study was to describe the severity and duration of postoperative pain experienced by children undergoing elective head and neck procedures (primary outcomes). Behavioral disturbance, nausea and vomiting, parental satisfaction, and medical reattendance rates were also measured (secondary outcomes). METHOD: Parents of children (0-18 years) undergoing common head and neck operations were invited to participate. Pain scores on the day of surgery and each day post discharge were collected via multiple telephone interviews. Data collected included pain levels, analgesia prescribed and given, behavioral disturbance rates, and nausea and vomiting scores. Follow-up was continued until pain resolved. RESULTS: Two hundred and fifty-one patients were analyzed (50 adenoidectomy, 51 adenotonsillectomy, 19 myringoplasty, 52 myringotomy, 43 strabismus, and 36 tongue tie divisions). On the day of surgery myringoplasty, strabismus surgery, and adenotonsillectomy patients on average had moderate pain, whereas adenoidectomy, tongue tie, and myringotomy patients had mild pain. Adenotonsillectomy patients continued to have moderate pain for several days with pain lasting on average 9 days. From day 1 postoperatively mild pain was experienced in the other surgical groups with the average duration of pain varying from 1 to 3 days depending on the surgery performed. Frequency of behavioral issues closely followed pain scores for each group. Analgesic prescribing and regimes at home varied widely, both within and between the different surgical groups. Rates of nausea and vomiting following discharge were low in all groups. The overall unplanned medical reattendance rate was 16%. CONCLUSION: Adenotonsillectomy patients represent the biggest challenge in postoperative pain management of the head and neck surgeries evaluated. The low rates of pain, nausea, and vomiting reported in the days following surgery for the other procedures suggests that children can be cared for at home with simple analgesia. Discharge information and analgesia prescribing on discharge should be tailored to the operation performed.

Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease.

BACKGROUND & AIMS: Ubiquitination is a reversible protein modification involved in the major cellular processes that define cell phenotype and behaviour. Ubiquitin modifications are removed by a large family of proteases named deubiquitinases. The role of deubiquitinases in hepatic stellate cell (HSC) activation and their contribution to fibrogenesis are poorly defined. We have identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation, determined its function in activated HSC and its potential as a therapeutic target for fibrosis. METHODS: Deubiquitinase expression was determined in day 0 and day 10 HSC. Increased UCHL1 expression was confirmed in human HSC and in an alcoholic liver disease (ALD) patient liver. The importance of UCHL1 in hepatic fibrosis was investigated in CCl4 and bile duct ligation injured mice using a pharmacological inhibitor (LDN 57444). The effects of UCHL1 inhibition on HSC proliferation were confirmed by Western blot and 3H thymidine incorporation. RESULTS: Here we report that pharmacological inhibition of UCHL1 blocks progression of established fibrosis in CCl4 injured mice. UCHL1 siRNA knockdown, LDN 57444 treatment, or HSC isolated from UCHL1(-/-) mice show attenuated proliferation in response to the mitogen, platelet-derived growth factor. Additionally, we observed changes in the phosphorylation of the cell cycle regulator retinoblastoma protein (Rb) in the absence of UCHL1 highlighting a potential mechanism for the reduced proliferative response. CONCLUSIONS: UCHL1 expression is highly upregulated upon HSC activation and is involved in the regulation of HSC proliferation. This study highlights therapeutic opportunities for pharmacological targeting of UCHL1 in chronic liver disease.