Deformation versus Sphericity in the Ground States of the Lightest Gold Isotopes.

The changes in mean-squared charge radii of neutron-deficient gold nuclei have been determined using the in-source, resonance-ionization laser spectroscopy technique, at the ISOLDE facility (CERN). From these new data, nuclear deformations are inferred, revealing a competition between deformed and spherical configurations. The isotopes ^{180,181,182}Au are observed to possess well-deformed ground states and, when moving to lighter masses, a sudden transition to near-spherical shapes is seen in the extremely neutron-deficient nuclides, ^{176,177,179}Au. A case of shape coexistence and shape staggering is identified in ^{178}Au which has a ground and isomeric state with different deformations. These new data reveal a pattern in ground-state deformation unique to the gold isotopes, whereby, when moving from the heavy to light masses, a plateau of well-deformed isotopes exists around the neutron midshell, flanked by near-spherical shapes in the heavier and lighter isotopes-a trend hitherto unseen elsewhere in the nuclear chart. The experimental charge radii are compared to those from Hartree-Fock-Bogoliubov calculations using the D1M Gogny interaction and configuration mixing between states of different deformation. The calculations are constrained by the known spins, parities, and magnetic moments of the ground states in gold nuclei and show a good agreement with the experimental results.

Utility of 3D printed models as adjunct in acetabular fracture teaching for Orthopaedic trainees.

OBJECTIVE: To evaluate the use of 3-D printed models as compared to didactic lectures in the teaching of acetabular fractures for Orthopaedic trainees. METHODS: This was a randomised prospective study conducted in a tertiary hospital setting which consisted of 16 Orthopaedic residents. Ten different cases of acetabular fracture patterns were identified and printed as 3-D models. The baseline knowledge of orthopaedic residents regarding acetabular fracture classification and surgical approach was determined by an x-ray based pre-test. Trainees were then randomly assigned into two groups. Group I received only lectures. Group II were additionally provided with 3-D printed models during the lecture. Participants were then assessed for comprehension and retention of teaching. RESULTS: Sixteen trainees participated in the trial. Both Group 1 and 2 improved post teaching with a mean score of 2.5 and 1.9 to 4.4 and 6 out of 10 respectively. The post test score for fracture classification and surgical approach were significantly higher for 3-D model group (p < 0.05). Trainees felt that the physical characteristics of the 3-D models were a good representation of acetabular fracture configuration, and should be used routinely for teaching and surgical planning. CONCLUSION: 3-D printed model of real clinical cases have significant educational impact compared to lecture-based learning towards improving young trainees' understanding of complex acetabular fractures.

Accuracy of contrast-enhanced CT and predictive factors for extracapsular spread in unknown primary head and neck squamous cell cancer.

AIM: To determine the accuracy of contrast-enhanced computed tomography (CECT) for nodal extracapsular spread (ECS) and identify predictive radiological signs and clinicopathological features for ECS in unknown-primary head and neck squamous cell cancer (UPHNSCC). MATERIALS AND METHODS: The CECT imaging of patients who underwent primary neck dissection for UPHNSCC during 2011-2015 was analysed. The largest pathological-looking node at each radiologically involved level was evaluated in consensus by two head and neck radiologists. Parameters included longest diameter, margin sharpness, haziness in adjacent fat, necrosis, and loss of fat plane with adjacent structures. Independent assessment was also made regarding the presence/absence of ECS. Findings and clinicopathological parameters were correlated with histopathology. RESULTS: Thirty-one patients with 39 neck levels had metastatic nodal involvement determined on CECT. Confirmed ECS was found at 26 levels in 23 patients. Sensitivity of radiological assessment for ECS by nodal level was 81-85% (95% confidence interval [CI]=65-93%) and specificity 46-54% (95% CI=19-81%); kappa 0.87. On univariate analysis based on the largest involved node per patient, longest diameter being ≥30 mm (p=0.007), haziness in adjacent fat (p=0.023), increasing age (p=0.006), and more advanced pathological nodal status (p=0.027) were statistically significantly associated with ECS. Haziness and increasing age were independent predictors on multivariate analysis (odds ratio [OR]=26.4 and 1.24). CONCLUSION: Expert assessment of ECS on CECT had good sensitivity with excellent interobserver agreement. A longest nodal diameter of ≥30 mm, haziness in the surrounding fat on CECT, advanced pathological nodal status, and advancing patient age were significantly associated with ECS in UPHNSCC patients, findings not previously reported.

Cyclin-dependent kinase 7 is a therapeutic target in high-grade glioma.

High-grade glioma (HGG) is an incurable brain cancer. The transcriptomes of cells within HGG tumors are highly heterogeneous. This renders the tumors unresponsive or able to adapt to therapeutics targeted at single pathways, thereby causing treatment failure. To overcome this, we focused on cyclin-dependent kinase 7 (CDK7), a ubiquitously expressed molecule involved in two major drivers of HGG pathogenesis: cell cycle progression and RNA polymerase-II-based transcription. We tested the activity of THZ1, an irreversible CDK7 inhibitor, on patient-derived primary HGG cell lines and ex vivo HGG patient tissue slices, using proliferation assays, microarray analysis, high-resolution respirometry, cell cycle analysis and in vivo tumor orthografts. The cellular processes affected by CDK7 inhibition were analyzed by reverse transcriptase-quantitative PCR, western blot, flow cytometry and immunofluorescence. THZ1 perturbed the transcriptome and disabled CDK activation, leading to cell cycle arrest at G2 and DNA damage. THZ1 halted transcription of the nuclear-encoded mitochondrial ribosomal genes, reducing mitochondrial translation and oxidative respiration. It also inhibited the expression of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFR-α), reducing signaling flux through the AKT, extracellular-signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) downstream pathways. Finally, THZ1 disrupted nucleolar, Cajal body and nuclear speckle formation, resulting in reduced cytosolic translation and malfunction of the spliceosome and thus leading to aberrant mRNA processing. These findings indicate that CDK7 is crucial for gliomagenesis, validate CDK7 as a therapeutic target and provide new insight into the cellular processes that are affected by THZ1 and induce antitumor activity.

Exploring men's perceptions of a community-based men's shed programme in England.

Background: Sheds have been used in Australia for decades as an intervention to try and promote 'health by stealth' among men by providing a social space for those who may be particularly vulnerable to poor mental health. Little is known about the impact of men's sheds in England. Methods: Members of 19 sheds from one local authority area were invited to participate in focus groups to explore their perceptions of their shed. In total, 32 men participated in five focus groups which were analysed using applied thematic analysis. Results: While some sheds run activities, the main driving factor of sheds was the social aspect, with many coming along for nothing more than a chat and a cup of tea, allowing men to recapture lost social networks from their working days. However, it was felt that there could be more formal links forged between individual groups, which may result in a better range of activities on offer. Conclusions: This study indicates that the shed can be an effective way of reducing social isolation in older men. However, further work is needed to understand what impact the shed has on physical and mental well-being.

The effect of physical fatigue on oscillatory dynamics of the sensorimotor cortex.

AIM: While physical fatigue is known to arise in part from supraspinal mechanisms within the brain, exactly how brain activity is modulated during fatigue is not well understood. Therefore, this study examined how typical neural oscillatory responses to voluntary muscle contractions were affected by fatigue. METHODS: Eleven healthy adults (age 27 ± 4 years) completed two experimental sessions in a randomized crossover design. Both sessions first assessed baseline maximal voluntary isometric wrist-flexion force (MVFb ). Participants then performed an identical series of fourteen test contractions (2 × 100%MVFb , 10 × 40%MVFb , 2 × 100%MVFb ) both before and after one of two interventions: forty 12-s contractions at 55%MVFb (fatigue intervention) or 5%MVFb (control intervention). Magnetoencephalography (MEG) was used to characterize both the movement-related mu and beta decrease (MRMD and MRBD) and the post-movement beta rebound (PMBR) within the contralateral sensorimotor cortex during the 40%MVFb test contractions, while the 100%MVFb test contractions were used to monitor physical fatigue. RESULTS: The fatigue intervention induced a substantial physical fatigue that endured throughout the post-intervention measurements (28.9-29.5% decrease in MVF, P < 0.001). Fatigue had a significant effect on both PMBR (anova, session × time-point interaction: P = 0.018) and MRBD (P = 0.021): the magnitude of PMBR increased following the fatigue but not the control interventions, whereas MRBD was decreased post-control but not post-fatigue. Mu oscillations were unchanged throughout both sessions. CONCLUSION: Physical fatigue resulted in an increased PMBR, and offset attenuations in MRBD associated with task habituation.

A Coproduction Community Based Approach to Reducing Smoking Prevalence in a Local Community Setting.

Research highlights that asset-based community development where local residents become equal partners in service development may help promote health and well-being. This paper outlines baseline results of a coproduction evaluation of an asset-based approach to improving health and well-being within a small community through promoting tobacco control. Local residents were recruited and trained as community researchers to deliver a smoking prevalence survey within their local community and became local health champions, promoting health and well-being. The results of the survey will be used to inform health promotion activities within the community. The local smoking prevalence was higher than the regional and national averages. Half of the households surveyed had at least one smoker, and 63.1% of children lived in a smoking household. Nonsmokers reported higher well-being than smokers; however, the differences were not significant. Whilst the community has a high smoking prevalence, more than half of the smokers surveyed would consider quitting. Providing smoking cessation advice in GP surgeries may help reduce smoking prevalence in this community. Work in the area could be done to reduce children's exposure to smoking in the home.

Can a theoretical framework help to embed alcohol screening and brief interventions in an endoscopy day-unit?

INTRODUCTION AND AIMS: The National Institute for Health Care and Excellence recommend that alcohol screening and brief intervention (ASBI) should be routinely implemented in secondary care. This study used theoretical frameworks to understand how health professionals can be supported to adapt their behaviour and clinical practice. DESIGN AND METHODS: Staff training and support was conducted using theoretical frameworks. A 12-week study, delivering ASBI was carried out as part of routine practice in an endoscopy day-unit. Anonymised patient data were collected using the Alcohol Use Disorders Identification Tool (AUDIT) and whether patients received a brief intervention. Staff completed the Shortened Alcohol and Alcohol Problems Perceptions Questionnaire at three time points and took part in a focus group both pre and post study. RESULTS: For staff, levels or role adequacy, role legitimacy, motivation to discuss alcohol, security in their role, job satisfaction and commitment to working with patients who drink increased during the time of the study. 1598 individual patients were seen in the department in the timeframe. Of these, 1180 patients were approached (74%); 18% (n=207) of patients were AUDIT positive. DISCUSSION: This study has shown that it is possible to reach a high number of patients in a busy hospital out-patient department and deliver ASBI by working with staff using theoretical frameworks for training. Embedding evidence-based public health interventions into routine clinical environments is complex. The social system in which professionals operate requires consideration alongside individual professionals' real and perceived barriers and facilitators to change.

Calf Compartment Syndrome associated with the Use of an Intra-osseous Line in an Adult Patient: A Case Report.

We present a case of a lower limb compartment syndrome associated with the use of an intra-osseous line inserted into the proximal tibia in an adult patient. An unconscious 59-year old male with multiple injuries presented to our Emergency Department after a road traffic accident. Bilateral proximal tibial intra osseous-lines were inserted due to poor venous access. After resuscitation his left leg was noted to be tense and swollen with absent pulses. Acute compartment syndrome was diagnosed both clinically and with compartment pressure measurement. Two incision fasciotomy on his left lower leg was performed. Intra osseous-lines in the proximal tibia are increasingly used in adult patients in the pre-hospital setting by paramedics and emergency physicians. Their use, along with the possible complications of these devices, such as the development of compartment syndrome or osteomyelitis leading to amputation, is well reported in the paediatric literature. To the best of our knowledge, there have not been any previous reports of complications in the adult patient. We present a case of lower leg compartment syndrome developing from the use of an intra-osseous line in the proximal tibia in an adult patient. With the increasing use of intra-osseous lines in adult patients, clinicians should be aware of the possibility of developing compartment syndrome which may lead to disability or amputation in severe cases.

The predictive value of structured ultrasonographic staging for thyroid nodules.

BACKGROUND: 'R staging' is a new ultrasonographic scoring system developed and used by our specialist head and neck radiologist for reporting sonographic risk of malignancy to those at our thyroid multidisciplinary team meeting. This study aimed to: classify the R staging system, examine its relationship with the eventual histopathological diagnosis and define its clinical utility. METHODS: The pre-operative ultrasound scans of 78 patients were assigned an R status by our specialist head and neck radiologist. The final histopathology report for each thyroid nodule was used as the 'gold standard' for analysis. RESULTS: When thyroid nodules were classified as low risk (R stages 1-3) or high risk (R stages 4-5) for malignancy, the sensitivity of R staging was 74.2 per cent and specificity was 80.9 per cent. An R5 status was 100 per cent predictive of malignancy. CONCLUSION: Our results compare favourably with other suggested ultrasonographic staging systems for thyroid nodules.

Divergence in ectomycorrhizal communities with foreign Douglas-fir populations and implications for assisted migration.

Assisted migration of forest trees has been widely proposed as a climate change adaptation strategy, but moving tree populations to match anticipated future climates may disrupt the geographically based, coevolved association suggested to exist between host trees and ectomycorrhizal fungal (EMF) communities. We explored this issue by examining the consistency of EMF communities among populations of 40 year-old Douglas-fir (Pseudotsuga menziesii var. menziesii) trees in a common-garden field trial using four provenances from contrasting coastal climates in southwestern British Columbia. Considerable variation in EMF community composition within test sites was found, ranging from 0.38 to 0.65 in the mean similarity index, and the divergence in EMF communities from local populations increased with site productivity. Clinal patterns in colonization success were detected for generalist and specialist EMF species on only the two productive test sites. Host population effects were limited to EMF species abundance rather than species loss, as richness per site averaged 15.0 among provenances and did not differ by transfer extent (up to 450 km), while Shannon's diversity index declined slightly. Large differences in colonization rates of specialist fungi, such as Tomentella stuposa and Clavulina cristata, raise the possibility that EMF communities maladapted to soil conditions contributed to the inferior growth of some host populations on productive sites. The results of the study suggest locally based specificity in host-fungal communities is likely a contributing factor in the outcome of provenance trials, and should be a consideration in analyzing seed-transfer effects and developing strategies for assisted migration.

The actin-associating protein Tm5NM1 blocks mesenchymal motility without transition to amoeboid motility.

Cell migration is an integral component of metastatic disease. The ability of cells to transit between mesenchymal and amoeboid modes of migration has complicated the development of successful therapies designed to target cell migration as a means of inhibiting metastasis. Therefore, investigations of the mechanisms that regulate cell migration and render cells stationary are necessary. Tropomyosins are actin-associating proteins that regulate the activity of several effectors of actin filament dynamics. Previously, we have shown that the tropomyosin isoform Tm5NM1 stabilizes actin filaments and inhibits cell migration in a two-dimensional culture system. Here, we show that Tm5NM1 inhibits the mesenchymal migration of multiple cell lines in an isoform-specific manner. Tm5NM1 stimulates the downregulation of Src kinase activity and a rounded or elliptical morphology in three-dimensional collagen gels, and cells have dramatically reduced capacity to form pseudopodia. Importantly, we find that Tm5NM1 inhibits both the mesenchymal to amoeboid and amoeboid to mesenchymal transitions. Collectively, our data suggest that mimicking the action of Tm5NM1 overexpression represents an approach for effectively inhibiting the mesenchymal mode of migration.

BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis.

BG-12, an immunomodulatory agent, reduces frequency of new gadolinium-enhancing (Gd+) lesions in relapsing multiple sclerosis (MS). This study reports the effect of 240 mg BG-12 orally three times daily (tid) for 24 weeks on the evolution of new Gd+ lesions to T1-hypointense lesions. Brain magnetic resonance imaging (MRI) scans from patients in placebo and 240 mg BG-12 tid arms of a phase 2b study were examined retrospectively. Included patients had at least one new Gd+ lesion from weeks 4 to 12. Week 24 scans were analyzed for number and proportion of new Gd+ lesions that evolved to T1-hypointense lesions. Eighteen patients receiving BG-12 and 38 patients receiving placebo were included in the analysis. The analysis tracked 147 new Gd+ lesions in patients from the BG-12 group and 221 Gd+ lesions in patients from the placebo group. The percentage of Gd+ lesions that evolved to T1-hypointense lesions was 34% lower with BG-12 treatment versus placebo (29%, BG-12; 44%, placebo; odds ratio 0.51; 95% confidence interval 0.43, 0.61; p < 0.0001). In addition to reducing frequency of new Gd+ lesions, BG-12 significantly reduced probability of their evolution to T1-hypointense lesions in patients with MS compared with placebo.

Cervical extraskeletal Ewing's sarcoma: case report demonstrating radiological features and management.

BACKGROUND: Extraskeletal Ewing's sarcoma is a rare tumour of mesenchymal origin, which is histologically similar to primary osseous Ewing's sarcoma. The majority of cases have been reported in the lower limb and paravertebral region, with a few cases reported in the neck. METHODS: We report a patient with extraskeletal Ewing's sarcoma presenting with a right-sided neck mass, vocal fold palsy and T1 nerve root involvement. The detection of characteristic features on computed tomography and magnetic resonance imaging scans, in conjunction with histological analysis, was required to make the diagnosis. RESULTS: Radiological imaging demonstrated that the tumour was infiltrating through the neural exit foramina of the lower cervical nerve roots, with encasement of the vertebral artery. The patient was managed with combination chemotherapy for systemic control and irradiation for local control. CONCLUSION: Extraskeletal Ewing's sarcoma has a propensity to occur in a paravertebral location, being found rarely in the cervical region, and has a predilection to infiltrate through neural exit formina. Computed tomography and magnetic resonance imaging are helpful in the diagnosis of this rare tumour.

Tropomyosins as interpreters of the signalling environment to regulate the local cytoskeleton.

A key regulator of cell morphology is the actin cytoskeleton and it has long been appreciated that the cytoskeleton is characteristically altered in cancer. Actin is organized into polymeric structures with distinct dynamics which in turn participate in a wide variety of cell processes including adhesion, migration, cell division and apoptosis. Despite displaying an altered actin cytoskeleton, transformed cells retain--and in many cases increase--their ability to adhere, move, divide and respond to apoptotic stimuli. Thus cancer cells maintain responsive actin cytoskeletons. Actin dynamics are regulated by numerous actin-binding proteins and chief among these are the tropomyosins which are core components of the microfilament. Recent advances in genomic and proteomic profiling confirm that Tm expression profiles are profoundly changed in transformed cells. It is therefore timely to review the role of Tms in the regulation of actin dynamics that pertain to crucial phenotypic changes in cancer. In this review we discuss how actin filaments containing different Tm isoforms respond to the activation of cell signalling pathways and consider the implications of this for cancer progression and therapy.

Pharmacokinetics, pharmacodynamics, and safety of a prostaglandin D2 receptor antagonist.

Laropiprant is a selective antagonist of the prostaglandin D(2) (PGD(2)) receptor subtype 1 (DP1). Three double-blind, randomized, placebo-controlled studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of laropiprant in healthy male volunteers. Single doses up to 900 mg and multiple doses up to 450 mg were generally well tolerated. Laropiprant exhibited dose-proportional pharmacokinetics. Oral absorption is rapid (T(max)=0.8-2.0 h) and the terminal half-life is approximately 12-18 h. The pharmacokinetics of laropiprant was not affected by food. Single doses of 6 mg and higher were effective in suppressing PGD(2)-induced cyclic AMP accumulation in platelets, demonstrating laropiprant target engagement with DP1. Laropiprant has detectable off-target antagonist effects at the thromboxane A(2) receptor but no clinically significant effect on collagen-induced platelet aggregation or bleeding times with multiple doses up to 200 mg.

Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1.

Niacin (nicotinic acid) reduces cardiovascular events in patients with dyslipidemia. However, symptoms associated with niacin-induced vasodilation (e.g., flushing) have limited its use. Laropiprant is a selective antagonist of the prostaglandin D(2) receptor subtype 1 (DP1), which may mediate niacin-induced vasodilation. The aim of this proof-of-concept study was to evaluate the effects of laropiprant (vs placebo) on niacin-induced cutaneous vasodilation. Coadministration of laropiprant 30, 100, and 300 mg with extended-release (ER) niacin significantly lowered flushing symptom scores (by approximately 50% or more) and also significantly reduced malar skin blood flow measured by laser Doppler perfusion imaging. Laropiprant was effective after multiple doses in reducing symptoms of flushing and attenuating the increased malar skin blood flow induced by ER niacin. In conclusion, the DP1 receptor antagonist laropiprant was effective in suppressing both subjective and objective manifestations of niacin-induced vasodilation.