First Probe of Sub-GeV Dark Matter beyond the Cosmological Expectation with the COHERENT CsI Detector at the SNS.

The COHERENT Collaboration searched for scalar dark matter particles produced at the Spallation Neutron Source with masses between 1 and 220 MeV/c^{2} using a CsI[Na] scintillation detector sensitive to nuclear recoils above 9 keV_{nr}. No evidence for dark matter is found and we thus place limits on allowed parameter space. With this low-threshold detector, we are sensitive to coherent elastic scattering between dark matter and nuclei. The cross section for this process is orders of magnitude higher than for other processes historically used for accelerator-based direct-detection searches so that our small, 14.6 kg detector significantly improves on past constraints. At peak sensitivity, we reject the flux consistent with the cosmologically observed dark-matter concentration for all coupling constants α_{D}<0.64, assuming a scalar dark-matter particle. We also calculate the sensitivity of future COHERENT detectors to dark-matter signals which will ambitiously test multiple dark-matter spin scenarios.

Measurement of Electron-Neutrino Charged-Current Cross Sections on

Using an 185-kg NaI[Tl] array, COHERENT has measured the inclusive electron-neutrino charged-current cross section on ^{127}I with pion decay-at-rest neutrinos produced by the Spallation Neutron Source at Oak Ridge National Laboratory. Iodine is one the heaviest targets for which low-energy (≤50 MeV) inelastic neutrino-nucleus processes have been measured, and this is the first measurement of its inclusive cross section. After a five-year detector exposure, COHERENT reports a flux-averaged cross section for electron neutrinos of 9.2_{-1.8}^{+2.1}×10^{-40} cm^{2}. This corresponds to a value that is ∼41% lower than predicted using the MARLEY event generator with a measured Gamow-Teller strength distribution. In addition, the observed visible spectrum from charged-current scattering on ^{127}I has been measured between 10 and 55 MeV, and the exclusive zero-neutron and one-or-more-neutron emission cross sections are measured to be 5.2_{-3.1}^{+3.4}×10^{-40} and 2.2_{-0.5}^{+0.4}×10^{-40} cm^{2}, respectively.

Measurement of the Coherent Elastic Neutrino-Nucleus Scattering Cross Section on CsI by COHERENT.

We measured the cross section of coherent elastic neutrino-nucleus scattering (CEvNS) using a CsI[Na] scintillating crystal in a high flux of neutrinos produced at the Spallation Neutron Source at Oak Ridge National Laboratory. New data collected before detector decommissioning have more than doubled the dataset since the first observation of CEvNS, achieved with this detector. Systematic uncertainties have also been reduced with an updated quenching model, allowing for improved precision. With these analysis improvements, the COHERENT Collaboration determined the cross section to be (165_{-25}^{+30})×10^{-40} cm^{2}, consistent with the standard model, giving the most precise measurement of CEvNS yet. The timing structure of the neutrino beam has been exploited to compare the CEvNS cross section from scattering of different neutrino flavors. This result places leading constraints on neutrino nonstandard interactions while testing lepton flavor universality and measures the weak mixing angle as sin^{2}θ_{W}=0.220_{-0.026}^{+0.028} at Q^{2}≈(50 MeV)^{2}.

First Measurement of Coherent Elastic Neutrino-Nucleus Scattering on Argon.

We report the first measurement of coherent elastic neutrino-nucleus scattering (CEvNS) on argon using a liquid argon detector at the Oak Ridge National Laboratory Spallation Neutron Source. Two independent analyses prefer CEvNS over the background-only null hypothesis with greater than 3σ significance. The measured cross section, averaged over the incident neutrino flux, is (2.2±0.7)×10^{-39} cm^{2}-consistent with the standard model prediction. The neutron-number dependence of this result, together with that from our previous measurement on CsI, confirms the existence of the CEvNS process and provides improved constraints on nonstandard neutrino interactions.

An investigation of the effects of procalcitonin testing on antimicrobial prescribing in respiratory tract infections in an Irish university hospital setting: a feasibility study.

BACKGROUND: Diagnostic uncertainty and a high prevalence of viral infections present unique challenges for antimicrobial prescribing for respiratory tract infections (RTIs). Procalcitonin (PCT) has been shown to support prescribing decisions and reduce antimicrobial use safely in patients with RTIs, but recent study results have been variable. METHODS: We conducted a feasibility study of the introduction of PCT testing in patients admitted to hospital with a lower RTI to determine if PCT testing is an effective and worthwhile intervention to introduce to support the existing antimicrobial stewardship (AMS) programme and safely decrease antimicrobial prescribing in patients admitted with RTIs. RESULTS: A total of 79 patients were randomized to the intervention PCT-guided treatment group and 40 patients to the standard care respiratory control group. The addition of PCT testing led to a significant decrease in duration of antimicrobial prescriptions (mean 6.8 versus 8.9 days, P = 0.012) and decreased length of hospital stay (median 7 versus 8 days, P = 0.009) between the PCT and respiratory control group. PCT did not demonstrate a significant reduction in antimicrobial consumption when measured as DDDs and days of therapy. CONCLUSIONS: PCT testing had a positive effect on antimicrobial prescribing during this feasibility study. The successful implementation of PCT testing in a randomized controlled trial requires an ongoing comprehensive education programme, greater integration into the AMS programme and delivery of PCT results in a timely manner. This feasibility study has shown that a larger randomized controlled trial would be beneficial to further explore the positive aspects of these findings.

The immunogenicity of ReFacto AF (moroctocog alfa AF-CC) in previously untreated patients with haemophilia A in the United Kingdom.

INTRODUCTION: Factor VIII inhibitor development is currently the most serious complication of the treatment of haemophilia A. Differences in manufacturing and the molecular structure of brands of recombinant factor VIII have led to speculation that concentrates may differ in immunogenicity. This has led to a regulatory focus on the immunogenicity of factor VIII concentrates both before and after licensure. AIM: To investigate the immunogenicity of ReFacto AF post licensure in a real-world setting in previously untreated patients (PUPs) treated exclusively with this product until at least 50 exposure days (EDs). METHODS: The United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) National Haemophilia Database (NHD) identified a consecutive cohort of patients with severe haemophilia A (<0.01 IU/L) whose first treatment was with ReFacto AF, monitored time to inhibitor development and described associated risk factors. RESULTS: One hundred and three boys reached 50 EDs within the study period, of whom 35 developed an inhibitor (P(t ≤ 50) = 0.33, [95% CI: 0.25-0.43]), of which 15 (P(t ≤ 50) = 0.16, [95% CI: 0.10-0.25]) were high titre. Inhibitors arose after a median (interquartile range) 11 (7-16) EDs. Inhibitors were significantly associated with high-risk mutations and non-significantly associated with non-white ethnicity. Inhibitors were negatively associated with a family history of haemophilia A. High-titre inhibitors were significantly associated with a family history of inhibitors. CONCLUSION: Inhibitor incidence in a single country population of ReFacto AF PUPs was similar to that previously described. Low- and high-titre inhibitors were detected after a similar number of EDs, contrasting with previous data, probably reflecting standardized inhibitor monitoring within the United Kingdom.

Intracranial haemorrhage in children with inherited bleeding disorders in the UK 2003-2015: A national cohort study.

INTRODUCTION: Intracranial haemorrhage in children with inherited bleeding disorders is a potentially life-threatening complication and presents a significant therapeutic challenge. AIM: To define the characteristics, management and outcomes of intracranial haemorrhage presenting in UK children ≤16 years of age with inherited bleeding disorders from 2003 to 2015. METHOD: Retrospective analysis of children treated at UK haemophilia centres. RESULTS: Of 66 children presenting with Intracranial haemorrhage (ICH), 82% had haemophilia A or B, 3% VWD and 15% a rare IBD. The IBD was a severe phenotype in 91%. The rates of ICH were 6.4 and 4.2 per 1000 patient years for haemophilia A and B, respectively. Median age at presentation was 4 months (33% neonates; 91% children <2 years of age). In neonates, delivery was spontaneous vaginal (SV) in 11, instrumental in 6, caesarean in 4 and unknown in 1. In children with haemophilia, the risk of ICH after instrumental delivery was 10.6 times greater than after SV delivery. Trauma was more common in children >2 years (67%) than in children 1 month to 2 years (18%; P = .027). Prior to ICH, only 4.5% of children were on prophylaxis. 6% of haemophiliacs had an inhibitor. The median duration of initial replacement therapy was 15 days. Mortality was 13.5%. Neurological sequelae occurred in 39% of survivors, being more common following intracerebral bleeding. In haemophilia survivors, 52% subsequently developed a FVIII inhibitor. CONCLUSION: Intracranial haemorrhage occurs most frequently in children with severe IBDs, during the first 2 years of life and in children not receiving prophylaxis. Intracranial haemorrhage often occurs without documented trauma.

A sexually dimorphic hypothalamic response to chronic high-fat diet consumption.

In this review, we discuss the observations that, following chronic high-fat diet (HFD) exposure, male mice have higher levels of saturated fatty acids (FAs) and total sphingolipids, whereas lower amounts of polyunsaturated FAs in the central nervous system (CNS) than females. Furthermore, males, when compared with female mice, have higher levels of inflammatory markers in the hypothalamus following exposure to HFD. The increase in markers of inflammation in male mice is possibly due to the reductions in proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and estrogen receptor alpha (ERα), which is not recapitulated in female mice. Consistently, hypothalamic inflammation is induced both in male and female ERα total-body knockout mice when exposed to a HFD, thus confirming the key role of ERα in the regulation of HFD-induced hypothalamic inflammation. Finally, the HFD-induced depletion of hypothalamic ERα is associated with dysregulation in metabolic homeostasis, as evidenced by reductions in glucose tolerance and decrements in myocardial function.

The incidence of factor VIII inhibitors in severe haemophilia A following a major switch from full-length to B-domain-deleted factor VIII: a prospective cohort comparison.

Although it has been suggested that switching of factor VIII (FVIII) products may increase inhibitor formation this is disputed. Half of UK patients changed rFVIII brands because of national contracting in 2010, presenting an opportunity to compare inhibitor incidence of switchers with non-switchers. Centres were requested to test all the patients for inhibitors prior to the switching date and 6-monthly thereafter. Positive and negative inhibitor test data were also collected to analyse for testing bias. A total of 1198 patients with severe haemophilia A and treated with Advate, Kogenate/Helixate or Refacto AF preswitch were included in the analysis, of whom 516 switched to Refacto-AF and 682 did not switch products. Five new inhibitors were reported amongst previously treated patients (>50 exposure days) with a median titre at the time of detection of 1.25 BU mL(-1) (IQR 0.7-23.05). One inhibitor occurred in a non-switcher using Kogenate, an incidence of 1.5 per 1000 treatment-years (95% CI 0.2-10.5). Four inhibitors arose in patients who had switched from Kogenate (two) or Advate (two) to ReFacto-AF, an incidence of 7.8 per 1000 treatment-years (95% CI 2.9-20.8). These incidence rates did not differ significantly from one another (incidence rate ratio 5.3 (95% CI 0.5-260.3) or from the historical rate of 6.05 inhibitors/1000 treatment-years (95% CI 5.18-7.06). Only one inhibitor (non-switcher) persisted. Non-switchers were significantly older (P = 0.03), and used significantly less FVIII per year (P = 0.005) prior to switching. Following switching, factor usage increased similarly (P = 0.53) in both groups. Switching from FLRFVIII to Refacto-AF (BDDRFVIII) was not associated with an increased inhibitor development.

Psychiatry resident-led tutorials increase medical student knowledge and improve national board of medical examiners shelf exam scores.

OBJECTIVES: Psychiatry residents have tremendous potential as educators. The authors envisioned residents as small-group tutors, efficiently assessing and correcting knowledge deficits using cases with discussion prompts and teaching points. They empirically tested whether this improves knowledge acquisition. METHODS: Senior residents delivered eight tutorials during clerkship, which covered child and adolescent psychiatry, anxiety, mood, psychotic, cognitive, and substance use disorders. A 50-item multiple-choice quiz was administered at the beginning and end of clerkship. National Board of Medical Examiners (NBME) shelf exam scores from intervention year were compared to the 4 years prior to resident involvement. RESULTS: Mean score on the initial quiz was 34.5 ± 3.7 and 41.8 ± 3.5 on second attempt (p < 0.001). Mean score for NBME psychiatry subject exam during intervention year was 83.2 ± 8.9 and for the four prior years was 78.0 ± 9.3, which was significant (p = 0.002). CONCLUSIONS: Resident-led tutorials provide an effective means of increasing psychiatric knowledge and improving performance on NBME subject exams.

[Primary interdisciplinary reconstruction of perineal defects to reduce wound complications after abdominoperineal resection]. / Interdisziplinäre, primäre Rekonstruktion des Perineums zur Vermeidung von Wundkomplikationen nach abdominoperinealer Rektumexstirpation.

BACKGROUND: Multimodal treatment options for ultra-low neoplasms of the rectum or anal cancer include chemotherapy, radical abdominoperineal resection and/or radiation. Primary wound closure increases the risk of perineal wound complications that require secondary revision. Perineal wound complications may trigger delay of adjacent tumor therapy and thus have an impact on rate of local recurrence and long-term survival for rectal cancer. Simultaneous primary reconstruction of the perineal defect has been shown to reduce the incidence of perineal wound complications as well as hospital stay which enables timely adjacent therapy and may improve prognosis. PATIENTS AND METHODS: This study was designed to retrospectively evaluate wound complications after abdominoperineal resection by comparing a group with and one without primary perineal reconstruction. Between 2005 and 2011, patients were analysed and divided into cohorts 1 and 2. Cohort 1 included n = 33 patients without primary perineal reconstruction. Cohort 2 included n = 4 patients with primary perineal reconstruction. Risk factors were identified for increased wound complications and delay of adjacent therapy. RESULTS: Subgroup analysis revealed that 18 out of 33 patients of cohort 1 had wound complications. In five cases, prolonged wound healing resulted in a delay of adjacent therapies. Four patients suffered from progression of tumour, 2 out of these 4 patients had a history of delayed adjacent therapy. The main risk factor for prolonged wound healing due to postoperative complications was a history of neoadjuvant treatment resulting in a rate of 64.7 %. Cohort 2 undergoing primary reconstruction presented without wound complications or delay in adjuvant therapy. DISCUSSION: A primary perineal reconstruction after APRE can reduce the rate of perineal wound complications. Furthermore, neoadjuvant treatment was shown to carry a major risk for wound complications. Patients after radio-/chemotherapy should undergo a primary reconstruction to prevent procedure-related perioperative morbidity. Subsequently, delays in adjuvant therapy, and prolonged hospital stay can be inhibited. Moreover, quality of life can be increased. The interdisciplinary approach aims at identifying high-risk patients for perineal wound complications who may benefit from primary reconstruction in order to reduce rate of wound complications with potential impact on rate of local recurrence. All these measures contribute to an optimized surgical standard.

Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

BACKGROUND: Species selectivity of DMXAA (5,6-dimethylxanthenone-4-acetic acid, Vadimezan) for murine cells over human cells could explain in part the recent disappointing phase III trials clinical results when preclinical studies were so promising. To identify analogues with greater human clinical potential, we compared the activity of xanthenone-4-acetic acid (XAA) analogues in murine or human cellular models. METHODS: Analogues with a methyl group systematically substituted at different positions of the XAA backbone were evaluated for cytokine induction in cultured murine or human leukocytes; and for anti-vascular effects on endothelial cells on matrigel. In vivo antitumour activity and cytokine production by stromal or cancer cells was measured in human A375 and HCT116 xenografts. RESULTS: Mono-methyl XAA analogues with substitutions at the seventh and eighth positions were the most active in stimulating human leukocytes to produce IL-6 and IL-8; and for inhibition of tube formation by ECV304 human endothelial-like cells, while 5- and 6-substituted analogues were the most active in murine cell systems. CONCLUSION: Xanthenone-4-acetic acid analogues exhibit extreme species selectivity. Analogues that are the most active in human systems are inactive in murine models, highlighting the need for the use of appropriate in vivo animal models in selecting clinical candidates for this class of compounds.

VEGF-A related SNPs: a cardiovascular context.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Currently, cardiovascular disease risk algorithms play a role in primary prevention. However, this is complicated by a lack of powerfully predictive biomarkers that could be observed in individuals before the onset of overt symptoms. A key potential biomarker for heart disease is the vascular endothelial growth factor (VEGF-A), a molecule that plays a pivotal role in blood vessel formation. This molecule has a complex biological role in the cardiovascular system due to the processes it influences, and its production is impacted by various CVD risk factors. Research in different populations has shown single nucleotide polymorphisms (SNPs) may affect circulating VEGF-A plasma levels, with some variants associated with the development of CVDs, as well as CVD risk factors. This minireview aims to give an overview of the VEGF family, and of the SNPs reported to influence VEGF-A levels, cardiovascular disease, and other risk factors used in CVD risk assessments.

Affective symptoms and intra-individual variability in the short-term course of cognitive functioning in bipolar disorder.

BACKGROUND: Few studies have examined the short-term course of cognitive impairments in bipolar disorder (BD). Key questions are whether trajectories in symptoms covary with cognitive function and whether BD is associated with increased intra-individual variability in cognitive abilities. METHOD: Forty-two out-patients with BD and 49 normal comparison (NC) subjects were administered a battery of neuropsychological tests at baseline, 6, 12 and 26 weeks, along with concurrent ratings of depressive and manic symptom severity. Mixed-effects regressions were used to model relationships between time, diagnosis and symptom severity on composite cognitive performance. Within-person variance in cognitive functioning across time was calculated for each subject. RESULTS: BD patients had significantly worse performance in cognitive ability across time points, but both groups showed significant improvement in cognitive performance over repeated assessments (consistent with expected practice effects). BD was associated with significantly greater intra-individual variability in cognitive ability than NCs; within-person variation was negatively related to baseline cognitive ability in BD but not NC subjects. Changes in affective symptoms over time did not predict changes in cognitive ability. CONCLUSIONS: Moderate changes in affective symptoms did not covary with cognitive ability in BD. The finding of elevated intra-individual variability in BD may reduce capacity to estimate trajectories of cognitive ability in observational and treatment studies.

Peer assisted learning in surgical skills laboratory training: a pilot study.

BACKGROUND: Peer assisted learning (PAL) has been rarely investigated in surgical skills training. AIMS: Describe feedback residents give peers on surgical skills with and without guidelines, determine the association between feedback and actual performance, evaluate resident satisfaction with PAL. METHOD: Participants evaluated peers using a validated knot-tying checklist and provided feedback on suturing without a guideline. Feedback comments were coded by type and an expert scored performance of each participant. Residents completed a satisfaction questionnaire. RESULTS: Comments were generally specific. Feedback was twice as likely with the use of a guideline. Specific feedback correlated significantly with expert knot-tying score but not suturing score. Most participants felt peer feedback was helpful and were motivated to practice surgical skills after PAL sessions. CONCLUSIONS: Surgical residents can provide high quality specific feedback to peers on surgical skills using performance guidelines. Further exploration of effective PAL methodology in surgical skills laboratory training is needed.

Decoupling a Cooper-pair box to enhance the lifetime to 0.2 ms.

We present results on a circuit QED experiment in which a separate transmission line is used to address a quasilumped element superconducting microwave resonator which is in turn coupled to an Al/AlO(x)/Al Cooper-pair box charge qubit. With our device, we find a strong correlation between the lifetime of the qubit and the inverse of the coupling between the qubit and the transmission line. At the smallest coupling we measured, the lifetime of the Cooper-pair box was T1=200 µs, which represents more than a twentyfold improvement in the lifetime of the Cooper-pair box compared with previous results. These results imply that the loss tangent in the AlO(x) junction barrier must be less than about 4×10⁻8 at 4.5 GHz, about 4 orders of magnitude less than reported in larger area Al/AlO(x)/Al tunnel junctions.

Results from a search for light-mass dark matter with a p-type point contact germanium detector.

We report on several features in the energy spectrum from an ultralow-noise germanium detector operated deep underground. By implementing a new technique able to reject surface events, a number of cosmogenic peaks can be observed for the first time. We discuss an irreducible excess of bulklike events below 3 keV in ionization energy. These could be caused by unknown backgrounds, but also dark matter interactions consistent with DAMA/LIBRA. It is not yet possible to determine their origin. Improved constraints are placed on a cosmological origin for the DAMA/LIBRA effect.

The risk of variant Creutzfeldt-Jakob disease among UK patients with bleeding disorders, known to have received potentially contaminated plasma products.

The risk of variant Creutzfeldt-Jakob disease (vCJD) from potentially infected plasma products remains unquantified. This risk has been assessed for 787 UK patients with an inherited bleeding disorder prospectively followed-up for 10-20 years through the UK Haemophilia Centre Doctors' Organisation (UKHCDO) Surveillance Study. These patients had been treated with any of 25 'implicated' clotting factor batches from 1987 to 1999, which included in their manufacture, plasma from eight donors who subsequently developed clinical vCJD. Variant CJD infectivity of these batches was estimated using plasma fraction infectivity estimates and batch-manufacturing data. Total potential vCJD infectivity received by each patient has been estimated by cumulating estimated infectivity from all doses received during their lifetime. Of 787 patients, 604 (77%) were followed-up for over 13 years following exposure to an implicated batch. For these 604 patients, the estimated vCJD risk is ≥ 1% for 595, ≥ 50% for 164 and 100% for 51. This is additional to background UK population risk due to dietary exposure. Of 604 patients, 94 (16%) received implicated batches linked to donors who developed clinical vCJD within 6 months of their donations. One hundred and fifty-one (25%) had received their first dose when under 10 years of age. By 1st January 2009, none of these patients had developed clinical vCJD. The absence of clinical vCJD cases in this cohort to date suggests that either plasma fraction infectivity estimates are overly precautionary, or the incubation period is longer for this cohort than for implicated cellular blood product recipients. Further follow-up of this cohort is needed.

Reinforcement of bio-apatite by zinc substitution in the incisor tooth of a prawn.

Various material-strengthening strategies have evolved in the cuticle and the feeding tools of arthropods. Of particular interest is the crustacean mandible, which is frequently reinforced with calcium phosphate, giving a minerology similar to that of human bones and teeth. We report here a biological strengthening method of apatite by Zn substitution, found in the incisor teeth of the freshwater prawn Macrobrachium rosenbergii. Nanoindentation measurements show a clear positive correlation between the Zn/Ca ratio and the stiffness and hardness of the composite. In the incisor, Zn-substituted apatite forms an internal vertical axis, extending from the sharp outer edges of the tooth to its basal segment. The substitution level in this zone (up to 40%) is very high compared with the levels achieved in synthetic ceramics (<20%). Finite element simulation suggests that the high-Zn axis acts as a unique internal load transfer element, directing stress from the biting cusps to the more compliant underlying layers. In light of the considerable research being invested in developing synthetic calcium phosphate derivatives for human bone and tooth grafts, the innovative mineralogy of the M. rosenbergii incisor may inspire beneficial biomimetic applications. STATEMENT OF SIGNIFICANCE: The controlled incorporation of impurities into biominerals is a widespread phenomenon in biomineralization that may pave the way to new classes of biomimetic materials. The present study reveals a biogenic mineral of zinc-substituted apatite found in the incisor teeth of a prawn. A clear correlation between zinc substitution level and stiffness and hardness, suggests that zinc substitution serves to mechanically reinforce the bioapatite. The spatial arrangement of the high-zinc apatite unveils a material-level adaptation strategy for tooth fortification, in which the rigid high-Zn structure servs as an internal load-transfer element that transmits the stress directly from the tooth's sharp cusps to the more compliant underlying layers.

Materials challenges and opportunities for quantum computing hardware.

Quantum computing hardware technologies have advanced during the past two decades, with the goal of building systems that can solve problems that are intractable on classical computers. The ability to realize large-scale systems depends on major advances in materials science, materials engineering, and new fabrication techniques. We identify key materials challenges that currently limit progress in five quantum computing hardware platforms, propose how to tackle these problems, and discuss some new areas for exploration. Addressing these materials challenges will require scientists and engineers to work together to create new, interdisciplinary approaches beyond the current boundaries of the quantum computing field.