Final Result of the Majorana Demonstrator's Search for Neutrinoless Double-ß Decay in

The Majorana Demonstrator searched for neutrinoless double-ß decay (0νßß) of ^{76}Ge using modular arrays of high-purity Ge detectors operated in vacuum cryostats in a low-background shield. The arrays operated with up to 40.4 kg of detectors (27.2 kg enriched to ∼88% in ^{76}Ge). From these measurements, the Demonstrator has accumulated 64.5 kg yr of enriched active exposure. With a world-leading energy resolution of 2.52 keV FWHM at the 2039 keV Q_{ßß} (0.12%), we set a half-life limit of 0νßß in ^{76}Ge at T_{1/2}>8.3×10^{25} yr (90% C.L.). This provides a range of upper limits on m_{ßß} of (113-269) meV (90% C.L.), depending on the choice of nuclear matrix elements.

LINC01013 Is a Determinant of Fibroblast Activation and Encodes a Novel Fibroblast-Activating Micropeptide.

Myocardial fibrosis confers an almost threefold mortality risk in heart disease. There are no prognostic therapies and novel therapeutic targets are needed. Many thousands of unannotated small open reading frames (smORFs) have been identified across the genome with potential to produce micropeptides (< 100 amino acids). We sought to investigate the role of smORFs in myocardial fibroblast activation.Analysis of human cardiac atrial fibroblasts (HCFs) stimulated with profibrotic TGFß1 using RNA sequencing (RNA-Seq) and ribosome profiling (Ribo-Seq) identified long intergenic non-coding RNA LINC01013 as TGFß1 responsive and containing an actively translated smORF. Knockdown of LINC01013 using siRNA reduced expression of profibrotic markers at baseline and blunted their response to TGFß1. In contrast, overexpression of a codon-optimised smORF invoked a profibrotic response comparable to that seen with TGFß1 treatment, whilst FLAG-tagged peptide associated with the mitochondria.Together, these data support a novel LINC01013 smORF micropeptide-mediated mechanism of fibroblast activation. TGFß1 stimulation of atrial fibroblasts induces expression of LINC01013, whose knockdown reduces fibroblast activation. Overexpression of a smORF contained within LINC01013 localises to mitochondria and activates fibroblasts.

A cryogenic continuously rotating half-wave plate mechanism for the POLARBEAR-2b cosmic microwave background receiver.

We present the design and laboratory evaluation of a cryogenic continuously rotating half-wave plate (CHWP) for the POLARBEAR-2b (PB-2b) cosmic microwave background receiver, the second installment of the Simons Array. PB-2b will observe at 5200 m elevation in the Atacama Desert of Chile in two frequency bands centered at 90 GHz and 150 GHz. In order to suppress atmospheric 1/f noise and mitigate systematic effects that arise when differencing orthogonal detectors, PB-2b modulates linear sky polarization using a CHWP rotating at 2 Hz. The CHWP has a 440 mm clear aperture diameter and is cooled to ≈50 K in the PB-2b receiver cryostat. It consists of a low-friction superconducting magnetic bearing and a low-torque synchronous electromagnetic motor, which together dissipate <2 W. During cooldown, a grip-and-release mechanism centers the rotor to <0.5 mm, and during continuous rotation, an incremental optical encoder measures the rotor angle with a noise level of 0.1 µrad/Hz. We discuss the experimental requirements for the PB-2b CHWP, the designs of its various subsystems, and the results of its evaluation in the laboratory. The presented CHWP has been deployed to Chile and is expected to see first light on PB-2b in 2020 or 2021.

Quantitative comparison of two-dimensional and three-dimensional strain measurement using MRI feature tracking in repair Fontan patients and normal child volunteers.

BACKGROUND: The accuracy of 2D and 3D strain analyses was evaluated by comparing strain and cardiac function parameters in Fontan repair patients and normal child volunteers. METHODS: We retrospectively enrolled 32 patients with Fontan circulation and 32 child volunteers who had undergone clinical cardiac magnetic resonance (CMR) assessment of the dominant ventricle with a 1.5-Tesla MRI scanner. Global and regional strain (2D and 3D) of the dominant ventricle in both groups was assessed using CMR feature-tracking. Correlations between cardiac function and strain data were assessed using Pearson's correlation coefficient values. The intraclass correlation coefficient (ICC) and coefficient of variation (CoV) were determined to evaluate repeatability and agreement. RESULTS: The 2D GLS showed significant differences between the Fontan repair patients and volunteers (- 16.49 ± 5.00 vs. -19.49 ± 2.03; p = 0.002). The 2D GRS and 2D GCS showed no significant differences between two groups. 2D GRS: 38.96 ± 14.48 vs. 37.46 ± 7.77; 2D GCS: - 17.64 ± 5.00 vs. -16.89 ± 2.96, respectively; p > 0.05). The 3D global radial strain (GRS), global circumferential strain (GCS), and global longitudinal strain (GLS) showed significant differences between the Fontan repair patients and volunteers (3D GRS: 36.35 ± 16.72 vs. 44.96 ± 9.98; 3D GLS: - 8.86 ± 6.84 vs. -13.67 ± 2.44; 3D GCS: - 13.70 ± 7.84 vs. -18.01 ± 1.78; p < 0.05, respectively). The ejection fraction (EF) and 3D GCS were significantly associated (r = - 0.491, p = 0.004). The 3D GCS showed correlations with the indexed end-diastolic volume (EDV) (r = 0.523, p = 0.002) and indexed end-systolic volume (ESV) (r = 0.602, p < 0.001). 3D strain showed good reproducibility, with GCS showing the best inter-observer agreement (ICC = 0.87 and CoV = 5.15), followed by GLS (ICC = 0.84 and CoV = 5.36). CONCLUSIONS: 3D GCS is feasible, highly reproducible, and strongly correlated with conventional cardiac function measures. 3D GCS assessments may be useful for monitoring abnormal myocardial motion in patients with Fontan circulation.

Pollination and resource limitation as interacting constraints on almond fruit set.

Pollination and resource availability are factors determining reproductive success of plants, and in agriculture these factors influence yield of fruit-bearing crops. Our understanding of the importance of crop pollination is fast improving, but less is known about how the interaction between pollination and resources constrains fruit production. We conducted an experiment with almond trees (Prunus dulcis) to examine how the number of flowers, light availability and competition for resources affected nut (fruit) production on individual spurs (fruit-bearing structures) exposed to open-pollination or hand-pollination. We found a positive relationship between flower number and nut number on spurs with up to four flowers, but no further benefit after four flowers, suggesting a resource threshold expressed by individual spurs. Spurs with few flowers increased the conversion rate of flowers to nuts when supplemented with hand-pollination, but spurs with more flowers were more likely to achieve the threshold number of nuts even under open-pollination. Our experiment included a further treatment involving spraying whole trees with pollen. This treatment reduced nut production by spurs with many flowers and high light availability, suggesting competition is experienced by well-resourced spurs when resources need to be shared among developing nuts across the whole tree. Our study supports the hypothesis that excess flower production in fruit trees increases the potential for fruit production when pollinator and resource availability is variable (bet-hedging). Spurs with more flowers typically produce more nuts (within a limited range), but only if both resources and pollen supply increase with flower number. For almond growers, a focus on maintaining high flower numbers, especially in high light regions of the canopy, is the foundation for high levels of production. Strategies to lift flower number and light are complicated by trade-offs inherent in tree architecture and orchard design. However, fruit set would be lifted above that achieved by current practice by an increase in the pollination rate of flowers.

Search for Neutrinoless Double-ß Decay in

The Majorana Collaboration is operating an array of high purity Ge detectors to search for neutrinoless double-ß decay in ^{76}Ge. The Majorana Demonstrator comprises 44.1 kg of Ge detectors (29.7 kg enriched in ^{76}Ge) split between two modules contained in a low background shield at the Sanford Underground Research Facility in Lead, South Dakota. Here we present results from data taken during construction, commissioning, and the start of full operations. We achieve unprecedented energy resolution of 2.5 keV FWHM at Q_{ßß} and a very low background with no observed candidate events in 9.95 kg yr of enriched Ge exposure, resulting in a lower limit on the half-life of 1.9×10^{25} yr (90% C.L.). This result constrains the effective Majorana neutrino mass to below 240-520 meV, depending on the matrix elements used. In our experimental configuration with the lowest background, the background is 4.0_{-2.5}^{+3.1} counts/(FWHM t yr).

Effects of a large wildfire on vegetation structure in a variable fire mosaic.

Management guidelines for many fire-prone ecosystems highlight the importance of maintaining a variable mosaic of fire histories for biodiversity conservation. Managers are encouraged to aim for fire mosaics that are temporally and spatially dynamic, include all successional states of vegetation, and also include variation in the underlying "invisible mosaic" of past fire frequencies, severities, and fire return intervals. However, establishing and maintaining variable mosaics in contemporary landscapes is subject to many challenges, one of which is deciding how the fire mosaic should be managed following the occurrence of large, unplanned wildfires. A key consideration for this decision is the extent to which the effects of previous fire history on vegetation and habitats persist after major wildfires, but this topic has rarely been investigated empirically. In this study, we tested to what extent a large wildfire interacted with previous fire history to affect the structure of forest, woodland, and heath vegetation in Booderee National Park in southeastern Australia. In 2003, a summer wildfire burned 49.5% of the park, increasing the extent of recently burned vegetation (<10 yr post-fire) to more than 72% of the park area. We tracked the recovery of vegetation structure for nine years following the wildfire and found that the strength and persistence of fire effects differed substantially between vegetation types. Vegetation structure was modified by wildfire in forest, woodland, and heath vegetation, but among-site variability in vegetation structure was reduced only by severe fire in woodland vegetation. There also were persistent legacy effects of the previous fire regime on some attributes of vegetation structure including forest ground and understorey cover, and woodland midstorey and overstorey cover. For example, woodland midstorey cover was greater on sites with higher fire frequency, irrespective of the severity of the 2003 wildfire. Our results show that even after a large, severe wildfire, underlying fire histories can contribute substantially to variation in vegetation structure. This highlights the importance of ensuring that efforts to reinstate variation in vegetation fire age after large wildfires do not inadvertently reduce variation in vegetation structure generated by the underlying invisible mosaic.

Primary care REFerral for EchocaRdiogram (REFER) in heart failure: a diagnostic accuracy study.

BACKGROUND: Symptoms of breathlessness, fatigue, and ankle swelling are common in general practice but deciding which patients are likely to have heart failure is challenging. AIM: To evaluate the performance of a clinical decision rule (CDR), with or without N-Terminal pro-B type natriuretic peptide (NT-proBNP) assay, for identifying heart failure. DESIGN AND SETTING: Prospective, observational, diagnostic validation study of patients aged >55 years, presenting with shortness of breath, lethargy, or ankle oedema, from 28 general practices in England. METHOD: The outcome was test performance of the CDR and natriuretic peptide test in determining a diagnosis of heart failure. The reference standard was an expert consensus panel of three cardiologists. RESULTS: Three hundred and four participants were recruited, with 104 (34.2%; 95% confidence interval [CI] = 28.9 to 39.8) having a confirmed diagnosis of heart failure. The CDR+NT-proBNP had a sensitivity of 90.4% (95% CI = 83.0 to 95.3) and specificity 45.5% (95% CI = 38.5 to 52.7). NT-proBNP level alone with a cut-off <400 pg/ml had sensitivity 76.9% (95% CI = 67.6 to 84.6) and specificity 91.5% (95% CI = 86.7 to 95.0). At the lower cut-off of NT-proBNP <125 pg/ml, sensitivity was 94.2% (95% CI = 87.9 to 97.9) and specificity 49.0% (95% CI = 41.9 to 56.1). CONCLUSION: At the low threshold of NT-proBNP <125 pg/ml, natriuretic peptide testing alone was better than a validated CDR+NT-proBNP in determining which patients presenting with symptoms went on to have a diagnosis of heart failure. The higher NT-proBNP threshold of 400 pg/ml may mean more than one in five patients with heart failure are not appropriately referred. Guideline natriuretic peptide thresholds may need to be revised.

A Randomised Controlled Trial of Treatment for Post-Stroke Homonymous Hemianopia: Screening and Recruitment.

The authors report the screening process and recruitment figures for the VISION (Visual Impairment in Stroke; Intervention Or Not) trial. This is a prospective, randomised, single-blinded, three-arm controlled trial in 14 UK acute hospital stroke units. Stroke teams identified stroke survivors suspected as having homonymous hemianopia. Interventions included Fresnel prisms versus visual search training versus standard care (information only). Primary outcome was change in visual field assessment from baseline to 26 weeks. Secondary measures included change in quality-of-life questionnaires. Recruitment opened in May 2011. A total of 1171 patients were screened by the local principal investigators. Of 1171 patients, 178 (15.2%) were eligible for recruitment: 87 patients (7.4%) provided consent and were recruited; 91 patients (7.8%) did not provide consent, and 993 of 1171 patients (84.8%) failed to meet the eligibility criteria. Almost half were excluded due to complete/partial recovery of hemianopia (43.6%; n = 511). The most common ineligibility reason was recovery of hemianopia. When designing future trials in this area, changes in eligibility criteria/outcome selection to allow more patients to be recruited should be considered, e.g., less stringent levels of visual acuity/refractive error. Alternative outcomes measurable in the home environment, rather than requiring hospital attendance for follow-up, could facilitate increased recruitment.

Hepatic drug transporters: the journey so far.

INTRODUCTION: The key role of transporter biology in both the manifestation and treatment of disease is now firmly established. Experiences of sub-optimal drug exposure due to drug-transporter interplay have supported incorporation of studies aimed at understanding the interactions between compounds and drug transporters much earlier in drug discovery. While drug transporters can impact the most pivotal pharmacokinetic parameter with respect to human dose and exposure projections, clearance, at a renal or hepatobiliary level, the latter will form the focus of this perspective. AREAS COVERED: A synopsis of guidelines on which transporters to study together with an overview of the currently available toolkit is presented. A perspective on when to conduct studies with various hepatic transporters is also provided together with structural "alerts" which should prompt early investigation. EXPERT OPINION: Great progress has been made in individual laboratories and via consortia to understand the role of drug transporters in disease, drug disposition, drug-drug interactions and toxicity. A systematic analysis of the value posed by the available approaches and an inter-lab comparison now seems warranted. The emerging ability to use physico-chemical properties to guide future screening cascades promises to revolutionise the efficiency of early drug discovery.

Can Coarse Woody Debris Be Used for Carbon Storage in Open Grazed Woodlands?

Carbon dioxide off-setting policy in the agricultural sector is focused on manipulating the terrestrial carbon cycle by reafforestation and increasing the retention of carbon within agricultural soils. We quantified the amount of carbon stored in the living and dead biomass and the surface soils of a previously grazed woodland ecosystem. We demonstrate that modification of coarse woody debris management could potentially store 8 to 15 t C ha. This large carbon pool raises the prospect that appropriate management of temperate woodlands to retain coarse woody debris and increase its volume into the future could achieve increased landscape carbon storage.

Interactive effects of fire and large herbivores on web-building spiders.

Altered disturbance regimes are a major driver of biodiversity loss worldwide. Maintaining or re-creating natural disturbance regimes is therefore the focus of many conservation programmes. A key challenge, however, is to understand how co-occurring disturbances interact to affect biodiversity. We experimentally tested for the interactive effects of prescribed fire and large macropod herbivores on the web-building spider assemblage of a eucalypt forest understorey and investigated the role of vegetation in mediating these effects using path analysis. Fire had strong negative effects on the density of web-building spiders, which were partly mediated by effects on vegetation structure, while negative effects of large herbivores on web density were not related to changes in vegetation. Fire amplified the effects of large herbivores on spiders, both via vegetation-mediated pathways and by increasing herbivore activity. The importance of vegetation-mediated pathways and fire-herbivore interactions differed for web density and richness and also differed between web types. Our results demonstrate that for some groups of web-building spiders, the effects of co-occurring disturbance drivers may be mostly additive, whereas for other groups, interactions between drivers can amplify disturbance effects. In our study system, the use of prescribed fire in the presence of high densities of herbivores could lead to reduced densities and altered composition of web-building spiders, with potential cascading effects through the arthropod food web. Our study highlights the importance of considering both the independent and interactive effects of disturbances, as well as the mechanisms driving their effects, in the management of disturbance regimes.

Should General Practitioners Issue a Sick Certificate to Employees Who Consult for Low Back Pain in Primary Care?

PURPOSE: Back pain is a common problem and has significant societal impact. Sickness certification is commonly issued to patients consulting their general practitioner with low back pain. The aim of this study was to investigate the association of certification for low back pain with clinical outcomes and cost consequences. METHODS: A prospective cohort study using linked questionnaire and medical record data from 806 low back pain patients in 8 UK general practices: comparison of 116 (14.4%) who received a sickness certificate versus 690 who did not receive certification. The primary clinical measure was the Roland and Morris Disability Questionnaire (RMDQ). Data on back pain consultation and work absenteeism were used to calculate healthcare and societal costs. RESULTS: Participants issued a sickness certificate had higher back-related disability at baseline consultation and 6-month follow-up [mean difference 3.1 (95% CI 1.8, 4.4) on the RMDQ], indicating worse health status. After fully adjusting for baseline differences, most changes in clinical outcomes at 6 months were not significantly different between study groups. Productivity losses were significantly higher for the certification group, with most absence occurring after the expected end of certification; mean difference in costs due to absenteeism over 6 months was £1,956 (95% CI £941, £3040). CONCLUSIONS: There was no clear evidence of a difference in clinical outcomes between individuals issued a sickness certificate and those not issued a certification for their back pain. With little overall contrast in clinical outcomes, policy makers and care providers may wish to draw on the likely difference in societal costs alongside issues in ethical and moral care in their consideration of patient care for low back pain.

Automating risk analysis of software design models.

The growth of the internet and networked systems has exposed software to an increased amount of security threats. One of the responses from software developers to these threats is the introduction of security activities in the software development lifecycle. This paper describes an approach to reduce the need for costly human expertise to perform risk analysis in software, which is common in secure development methodologies, by automating threat modeling. Reducing the dependency on security experts aims at reducing the cost of secure development by allowing non-security-aware developers to apply secure development with little to no additional cost, making secure development more accessible. To automate threat modeling two data structures are introduced, identification trees and mitigation trees, to identify threats in software designs and advise mitigation techniques, while taking into account specification requirements and cost concerns. These are the components of our model for automated threat modeling, AutSEC. We validated AutSEC by implementing it in a tool based on data flow diagrams, from the Microsoft security development methodology, and applying it to VOMS, a grid middleware component, to evaluate our model's performance.

Patient preferences for clinical follow-up after primary treatment for soft tissue sarcoma: a cross-sectional survey and discrete choice experiment.

BACKGROUND: Patients treated for soft tissue sarcoma (STS) require long-term follow-up to detect recurrent or metastatic disease, yet marked differences exist in clinical approaches to the length of follow-up, frequency of consultations and investigations undertaken at follow-up visits. There has been no published work assessing patient expectations or the acceptability of post-treatment follow-up strategies. This study aimed to assess the patient acceptability of different follow-up strategies following curative surgery for soft tissue sarcoma and to investigate the hypothetical levels of recurrence risk at which different follow-up regimes were acceptable. METHODS: Patients were recruited from the Royal Orthopaedic Hospital in Birmingham. The study used a cross-sectional survey incorporating a best-worst scaling discrete choice experiment to assess patient preferences regarding different aspects of follow-up. RESULTS: 132 patients participated (47% response). The nature of investigations undertaken during follow-up was the most important aspect of post-surgical care. Patients typically preferred appointments routinely consisting of clinical examination and chest X-ray, and for follow-up to remain in secondary care rather than general practice. CONCLUSION: Clear protocols for STS patient follow-up can improve consistency and equity of care. In determining the optimum follow-up plan for STS patients from the patient perspective, this study provides valuable information that should be considered alongside the clinical effectiveness of follow-up strategies to maximise patient outcomes and use NHS resources appropriately.

An empirical assessment of the focal species hypothesis.

Biodiversity surrogates and indicators are commonly used in conservation management. The focal species approach (FSA) is one method for identifying biodiversity surrogates, and it is underpinned by the hypothesis that management aimed at a particular focal species will confer protection on co-occurring species. This concept has been the subject of much debate, in part because the validity of the FSA has not been subject to detailed empirical assessment of the extent to which a given focal species actually co-occurs with other species in an assemblage. To address this knowledge gap, we used large-scale, long-term data sets of temperate woodland birds to select focal species associated with threatening processes such as habitat isolation and loss of key vegetation attributes. We quantified co-occurrence patterns among focal species, species in the wider bird assemblage, and species of conservation concern. Some, but not all, focal species were associated with high levels of species richness. One of our selected focal species was negatively associated with the occurrence of other species (i.e., it was an antisurrogate)-a previously undescribed property of nominated focal species. Furthermore, combinations of focal species were not associated with substantially elevated levels of bird species richness, relative to levels associated with individual species. Our results suggest that although there is some merit to the underpinning concept of the FSA, there is also a need to ensure that actions are sufficiently flexible because management tightly focused on a given focal species may not benefit some other species, including species of conservation concern, such of which might not occur in species-rich assemblages.

A randomised controlled trial to compare the clinical and cost-effectiveness of prism glasses, visual search training and standard care in patients with hemianopia following stroke: a protocol.

INTRODUCTION: Homonymous hemianopia is a common and disabling visual problem after stroke. Currently, prism glasses and visual scanning training are proposed to improve it. The aim of this trial is to determine the effectiveness of these interventions compared to standard care. METHODS AND ANALYSIS: The trial will be a multicentre three arm individually randomised controlled trial with independent assessment at 6 week, 12 week and 26 week post-randomisation. Recruitment will occur in hospital, outpatient and primary care settings in UK hospital trusts. A total of 105 patients with homonymous hemianopia and without ocular motility impairment, visual inattention or pre-existent visual field impairment will be randomised to one of three balanced groups. Randomisation lists will be stratified by site and hemianopia level (partial or complete) and created using simple block randomisation by an independent statistician. Allocations will be disclosed to patients by the treating clinician, maintaining blinding for outcome assessment. The primary outcome will be change in visual field assessment from baseline to 26 weeks. Secondary measures will include the Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual-5D and Short Form-12 questionnaires. Analysis will be by intention to treat. ETHICS AND DISSEMINATION: This study has been developed and supported by the UK Stroke Research Network Clinical Studies Group working with service users. Multicentre ethical approval was obtained through the North West 6 Research ethics committee (Reference 10/H1003/119). The trial is funded by the UK Stroke Association. Trial Registration: Current Controlled Trials ISRCTN05956042. Dissemination will consider usual scholarly options of conference presentation and journal publication in addition to patient and public dissemination with lay summaries and articles. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05956042.

Sentinel lymph node biopsy in vulval cancer: systematic review and meta-analysis.

BACKGROUND: The purpose of this study was to determine the accuracy of sentinel lymph node (SLN) biopsy with technetium 99 (99mTc) and/or blue dye-enhanced lymphoscintigraphy in vulval cancer. METHODS: Sensitive searches of databases were performed upto October 2013. Studies with at least 75% of women with FIGO stage IB or II vulval cancer evaluating SLN biopsy with 99mTc, blue dye or both with reference standard of inguinofemoral lymphadenectomy (IFL) or clinical follow-up were included. Meta-analyses were performed using Meta-Disc version 1.4. RESULTS: Of the 2950 references, 29 studies (1779 women) were included; most of them evaluated 99mTc combined with blue dye. Of these, 24 studies reported results for SLN followed by IFL, and 5 reported clinical follow-up only for SLN negatives. Pooling of all studies was inappropriate because of heterogeneity. Mean SLN detection rates were 94.0% for 99mTc, 68.7% for blue dye and 97.7% for both. SLN biopsy had pooled sensitivity of 95% (95% CI 92-98%) with negative predictive value (NPV) of 97.9% in studies using 99mTc/blue dye, ultrastaging and immunohistochemistry with IFL as reference. Pooled sensitivity for SLN with clinical follow-up for SLN-negatives was 91% (85-95%) with NPV 95.6%. Patients undergoing SLN biopsy experienced less morbidity than those undergoing IFL. CONCLUSIONS: Sentinel lymph node biopsy using 99mTC, blue dye and ultrastaging with immunohistochemistry is highly accurate when restricted to carefully selected patients, within a rigorous protocol, with close follow-up and where sufficient numbers for learning curve optimisation exist. Patients must make an informed choice between the slightly higher groin recurrence rates of SLN biopsy vs the greater morbidity of IFL.