Tritium Beta Spectrum Measurement and Neutrino Mass Limit from Cyclotron Radiation Emission Spectroscopy.

The absolute scale of the neutrino mass plays a critical role in physics at every scale, from the subatomic to the cosmological. Measurements of the tritium end-point spectrum have provided the most precise direct limit on the neutrino mass scale. In this Letter, we present advances by Project 8 to the cyclotron radiation emission spectroscopy (CRES) technique culminating in the first frequency-based neutrino mass limit. With only a cm^{3}-scale physical detection volume, a limit of m_{ß}<155 eV/c^{2} (152 eV/c^{2}) is extracted from the background-free measurement of the continuous tritium beta spectrum in a Bayesian (frequentist) analysis. Using ^{83m}Kr calibration data, a resolution of 1.66±0.19 eV (FWHM) is measured, the detector response model is validated, and the efficiency is characterized over the multi-keV tritium analysis window. These measurements establish the potential of CRES for a high-sensitivity next-generation direct neutrino mass experiment featuring low background and high resolution.

A novel protocol to induce mental fatigue.

Mental fatigue is a commonplace human experience which is the focus of a growing body of research. Whilst researchers in numerous disciplines have attempted to uncover the origins, nature, and effects of mental fatigue, the literature is marked by many contradictory findings. We identified two major methodological problems for mental fatigue research. First, researchers rarely use objective measures of mental fatigue. Instead, they rely heavily on subjective reports as evidence that mental fatigue has been induced in participants. We aimed to develop a task which led to not only a subjective increase in mental fatigue, but a corresponding performance decrement in the mentally fatiguing task as an objective measure. Secondly, current mental fatigue paradigms have low ecological validity - in most prior studies participants have been fatigued with a single repetitive task such as the n-back or Stroop. To move towards a more ecologically valid paradigm, our participants undertook a battery of diverse cognitive tasks designed to challenge different aspects of executive function. The AX-CPT, n-back, mental rotation, and visual search tasks were chosen to challenge response inhibition, working memory, spatial reasoning, and attention. We report results from 45 participants aged 19 to 63 years who completed a two-hour battery comprising four different cognitive tasks. Subjective fatigue ratings and task performance were measured at the beginning and end of the battery. Our novel method resulted in an increase in subjective ratings of fatigue (p < 0.001) and a reduction in task performance (p = 0.008). Future research into mental fatigue may benefit from using this task battery.

Management of superior mesenteric venous thrombus in cystic fibrosis related liver disease.

Abdominal pain is a common feature in patients with cystic fibrosis (CF) and CF related liver disease (CFLD). Superior mesenteric venous (SMV) thrombosis is an uncommon but important cause of abdominal pain. Management strategies are complicated by an underlying prothrombotic state and increased risk of bleeding from complications of CF and CFLD. This review addresses clinical presentation, detection and management options of an acute SMV thrombus in the context of CF.

Factors related to condomless anal intercourse between men who have sex with men: results from a European bio-behavioural survey.

BACKGROUND: Relationship status is an important factor associated with condomless anal intercourse (CAI) amongst men who have sex with men (MSM). METHODS: A multi-centre bio-behavioural survey with MSM was conducted in 13 European cities (n = 4901) exploring factors associated with CAI via bivariate and multivariate multilevel logistic regression analyses. RESULTS: Likelihood of CAI with casual partners was associated with being 'out' to a majority (AOR = 1.19;95% CI 1,1.42); knowing their HIV status (AOR = 1.86; 95% CI 1.25,2.76); using substances (1-2 AOR = 1.39; 95% CI 1.16,1.63, 2+ AOR = 1.81; 95% CI 1.35,2.42); being older (AOR = 0.98; 95% CI 0.97,0.99); successful sero-communication (AOR = 0.79; 95% CI 0.67,0.94); and, not having a recent HIV test (AOR = 0.78; 95% CI 0.66,0.92). CAI with steady partners was associated with successful sero-communication (AOR = 2.72; 95% CI 2.72,3.66); not having a recent HIV test (AOR = 1.26; 95% CI 1.09,1.46), and; being older (AOR = 0.99; 95% CI 0.98,0.99). CONCLUSIONS: Understandings of partner type and/or relationship status in relation to CAI amongst MSM can potentially play an important role in the development of culturally appropriate HIV/STI prevention and risk-reduction efforts targeting at-risk MSM. Our results speak to the need to consider segmented and tailored public health and health promotion initiatives for MSM with differing CAI behaviours and relationship profiles.

Effects of montmorency tart cherry (L. Prunus Cerasus) consumption on nitric oxide biomarkers and exercise performance.

The purpose of this study was to investigate the effects of Montmorency tart cherry juice (MC) on nitric oxide (NO) biomarkers, vascular function, and exercise performance. In a randomized, double-blind, placebo (PLA)-controlled, crossover study, 10 trained cyclists (mean ± SD; V˙O2peak 59.0 ± 7.0 mL/kg/min) acutely ingested 30 mL of either MC or PLA following dietary restrictions of polyphenol-rich compounds and completed 6-minutes moderate- and severe-intensity cycling bouts 1.5 hour post-ingestion on 2 occasions for each experimental condition. The severe-intensity cycling test was continued to exhaustion on 1 occasion and immediately followed by a 60-seconds all-out sprint on the other occasion. Blood pressure, pulse wave measures, tissue oxygenation index, and plasma nitrite concentration were assessed pre- and 1.5 hour post-ingestion. Time to exhaustion was not different between conditions (P > .05), but peak power over the first 20 seconds (363 ± 42 vs 330 ± 26 W) and total work completed during the 60-seconds all-out sprint (21 ± 3 vs 19 ± 3 kJ) were 10% higher in the MC trial compared to the PLA trial (P < .05). Systolic blood pressure was 5 ± 2 mm Hg lower 1.5 hour post-MC supplementation compared to PLA supplementation (P < .05). There were no differences in pulse wave measures, plasma nitrite concentration, or tissue oxygenation between the MC and PLA trials (P > .05). These results suggest that acute supplementation with MC can lower blood pressure and improve some aspects of exercise performance, specifically end-sprint performance, in trained cyclists.

Antifungal Activity of SCY-078 and Standard Antifungal Agents against 178 Clinical Isolates of Resistant and Susceptible Candida Species.

SCY-078 in vitro activity was determined for 178 isolates of resistant or susceptible Candida albicans, Candida dubliniensis, Candida glabrata, Candida krusei, Candida lusitaniae, and Candida parapsilosis, including 44 Candida isolates with known genotypic (FKS1 or FKS2 mutations), phenotypic, or clinical resistance to echinocandins. Results were compared to those for anidulafungin, caspofungin, micafungin, fluconazole, and voriconazole. SCY-078 was shown to have excellent activity against both wild-type isolates and echinocandin- and azole-resistant isolates of Candida species.

Fungal CYP51 Inhibitors VT-1161 and VT-1129 Exhibit Strong In Vitro Activity against Candida glabrata and C. krusei Isolates Clinically Resistant to Azole and Echinocandin Antifungal Compounds.

The in vitro activities of fungal CYP51 inhibitors VT-1161 and VT-1129 were determined for Candida glabrata (n = 34) and C. krusei (n = 50). C. glabrata isolates were screened for FKS gene mutations. All isolates were resistant clinically and/or in vitro to at least one standard antifungal compound. VT-1161 and VT-1129 MICs for all isolates were at least 5-fold below achievable human plasma levels for VT-1161. VT-1161 and VT-1129 are promising for the treatment of resistant C. glabrata and C. krusei infections.

Ralstonia infection in cystic fibrosis.

This study aimed to determine prevalence of Ralstonia spp. in cystic fibrosis patients, look for any evidence of cross infection and to describe clinical outcomes for patients infected by Ralstonia spp. Prevalence of Ralstonia spp. was calculated annually from 2008 to 2016. Pulsed-field gel electrophoresis was performed on ⩾1 sample from patients with an isolation of Ralstonia spp. between 2008 and 2016. A prospective, longitudinal observational study of adult patients was performed with 12 months follow-up from recruitment. Prevalence of Ralstonia spp. rose from 0·6% in 2008 to 2·4% in 2016. In total 12 out of 14 (86%) patients with ⩾1 isolation of Ralstonia spp. developed chronic infection. A pair and a group of three unrelated patients with epidemiological connections shared strains of Ralstonia mannitolilytica. Lung function of Ralstonia spp. infected patients was moderately to severely impaired. Prevalence of Ralstonia spp. is low but increasing. The risk of a patient developing chronic Ralstonia spp. infection following first acquisition is high and cross-infection may be possible. Whether Ralstonia spp. infection causes increased pulmonary exacerbation frequency and lung function decline needs to be evaluated in larger prospective studies.

Reduced oxygen cost of running is related to alignment of the resultant GRF and leg axis vector: A pilot study.

This pilot study investigated whether a 10-week running program (10wkRP), which reduced the oxygen cost of running, affected resultant ground reaction force (GRF), leg axis alignment, joint moment characteristics, and gear ratios. Ten novice, female runners completed a 10wkRP. Running kinematics and kinetics, in addition to oxygen consumption ( V ˙ O 2 ) during steady-state running, were recorded pre- and post-10wkRP. V ˙ O 2 decreased (8%) from pre-10wkRP to post-10wkRP. There was a better alignment of the resultant GRF and leg axis at peak propulsion post-10wkRP compared with pre-10wkRP (10.8 ± 4.9 vs 1.6 ± 1.2°), as the resultant GRF vector was applied 7 ± 0.6° (P = 0.008) more horizontally. There were shorter external ankle moment arms (24%) and smaller knee extensor moments (23%) at peak braking post-10wkRP. The change in V ˙ O 2 was associated with the change in alignment of the resultant GRF and leg axis (rs = 0.88, P = 0.003). As runners became more economical, they exhibited a more aligned resultant GRF vector and leg axis at peak propulsion. This appears to be a self-optimization strategy that may improve performance. Additionally, changes to external ankle moment arms indicated beneficial low gear ratios were achieved at the time of peak braking force.

Single-Electron Detection and Spectroscopy via Relativistic Cyclotron Radiation.

It has been understood since 1897 that accelerating charges must emit electromagnetic radiation. Although first derived in 1904, cyclotron radiation from a single electron orbiting in a magnetic field has never been observed directly. We demonstrate single-electron detection in a novel radio-frequency spectrometer. The relativistic shift in the cyclotron frequency permits a precise electron energy measurement. Precise beta electron spectroscopy from gaseous radiation sources is a key technique in modern efforts to measure the neutrino mass via the tritium decay end point, and this work demonstrates a fundamentally new approach to precision beta spectroscopy for future neutrino mass experiments.

Influence of hypoxia on the power-duration relationship during high-intensity exercise.

We investigated the influence of hypoxia on the asymptote (critical power, CP) and the curvature constant (W') of the hyperbolic power-duration relationship, as measured by both conventional and all-out testing procedures. 13 females completed 5 constant-power prediction trials and a 3-min all-out test to estimate CP and W', in both normoxia (N) and moderate hypoxia (H; FiO2=0.13). CP was significantly reduced in hypoxia compared to normoxia when estimated by conventional (H:132±17 vs. N:175±25 W; P<0.001) and all-out methods (H:134±23 vs. N:172±30 W; P<0.01). The W' was not significantly different in hypoxia compared to normoxia when established by conventional (H:12.3±2.7 vs. N:13.2±2.2 kJ) and all-out methods (H:12.0±2.6 vs. N:12.5±1.4 kJ). Estimates of CP and W' obtained with conventional and all-out methods were not significantly different either in normoxia or hypoxia. There was a significant relationship between the % change in CP relative to V̇(O2peak) and the % change in W' in normoxia compared to hypoxia (r=0.83, P<0.001; conventional test). Changes in the W' in hypoxia are related to changes in the CP relative to V̇(O2peak), suggesting that the W' may not be defined simply as an 'anaerobic' energy store.

The Effects of Chronic Nitrate Supplementation and the Use of Strong and Weak Antibacterial Agents on Plasma Nitrite Concentration and Exercise Blood Pressure.

Chlorhexidine-containing mouthwash (STRONG), which disturbs oral microflora, has been shown to diminish the rise in plasma nitrite concentration ([NO2-]) and attenuate the reduction in resting blood pressure (BP) typically seen after acute nitrate (NO3-) ingestion. We aimed to determine whether STRONG and weaker antiseptic agents attenuate the physiological effects of chronic NO3- supplementation using beetroot juice (BR). 12 healthy volunteers mouth-rinsed with STRONG, non-chlorhexidine mouthwash (WEAK) and deionised water (CON) 3 times a day, and ingested 70 mL BR (6.2 mmol NO3-), twice a day, for 6 days. BP (at rest and during 10 min of treadmill walking) and plasma and salivary [NO3-] and [NO2-] were measured prior to and on day 6 of supplementation. The change in salivary [NO3-] 4 h post final ingestion was higher (P<0.05) in STRONG (8.7±3.0 mM) compared to CON (6.3±0.9 mM) and WEAK (6.0±3.0 mM). In addition, the rise in plasma [NO2-] at 2 h was lower in STRONG compared with WEAK (by 89±112 nM) and CON (by 200±174 nM) and in WEAK compared with CON (all P<0.05). Changes in resting BP were not different between conditions (P>0.05). However, during treadmill walking, the increase in systolic and mean arterial BP was higher 4 h after the final nitrate bolus in STRONG compared with CON (P<0.05) but not WEAK. The results indicate that both strong and weak antibacterial agents suppress the rise in plasma [NO2-] observed following the consumption of a high NO3- diet and the former can influence the BP response during low-intensity exercise.

Establishment of invasive and non-invasive reporter systems to investigate American elm-Ophiostoma novo-ulmi interactions.

Dutch elm disease (DED), caused by ascomycete fungi in the Ophiostoma genus, is the most devastating disease of American elm (Ulmus americana) trees. Cerato ulmin (CU), a hydrophobin secreted by the fungus, has been implicated in the development of DED, but its role in fungal pathogenicity and virulence remains uncertain and controversial. Here, we describe reporter systems based on the CU promoter and three reporter proteins (GFP, GUS and LUC), developed as research tools for quantitative and qualitative studies of DED in vitro, in vivo and in planta. A strain of the aggressive species Ophiostoma novo-ulmi was transformed with the reporter constructs using Agrobacterium-mediated transformation and the fungal transformants, namely M75-GFP, M75-GUS and M75-LUC, were examined for mitotic stability after repeated subcultures. The intensity of GFP fluorescence was strong in M75-GFP spores and hyphae, allowing microscopic investigations of spore structure, fungal morphogenesis and fungal development. The interaction of M75-GFP and U. americana callus cells was explored with scanning laser confocal microscopy facilitating qualitative studies on fungal strategies for the invasion and penetration of elm cells. M75-GUS was generated to provide an invasive, yet quantitative approach to study fungal-plant interactions in vitro and in planta. The generation of M75-LUC transformants was aimed at providing a non-destructive quantitative approach to study the role of CU in vivo. The sensitivity, low background signal and linearity of LUC assays all predict a very reliable approach to investigate and re-test previously claimed roles of this CU in fungal pathogenicity. These reporter systems provide new tools to investigate plant-pathogen interactions in this complex pathosystem and may aid in better understanding the development of DED.

The effect of the weather on pulmonary exacerbations and viral infections among adults with cystic fibrosis.

The effect of changes in the weather on the respiratory health of patients with cystic fibrosis (CF) is unclear. We conducted a prospective study to determine the impact of climate and season on the incidence of viral respiratory infections (VRI) and pulmonary exacerbations (PEx) among adults with CF. Between December 2010 and April 2012, 98 adults with CF were followed for 12 months. Polymerase chain reaction assays for nine viruses were performed on sputum, nose and throat swabs every 2 months and additionally at onset of PEx. Hourly temperature and relative humidity measurements were recorded throughout the study. Statistical analysis utilized generalized estimating equation (GEE) models. Pre-specified criteria for VRI and PEx were met at 29% and 37% of visits, respectively. Rhinovirus accounted for 72% of identified viruses. Incidence of rhinovirus peaked in autumn while non-rhinovirus VRI peaked in winter. Rhinovirus was associated with increased mean temperatures (OR 1.07; p = 0.001), while non-rhinovirus VRI was associated with lower mean temperatures (OR 0.87; p < 0.001). PEx occurred frequently throughout the study with no clear seasonal pattern observed. There was no significant association between climate variables and the incidence of either PEx or antibiotic prescription. There is a seasonal pattern to VRI in adults with CF. The incidence of VRI but not PEx is associated with changes in ambient temperature.

A tissue engineering strategy for the treatment of avascular necrosis of the femoral head.

BACKGROUND & PURPOSE: Skeletal stem cells (SSCs) and impaction bone grafting (IBG) can be combined to produce a mechanically stable living bone composite. This novel strategy has been translated to the treatment of avascular necrosis of the femoral head. Surgical technique, clinical follow-up and retrieval analysis data of this translational case series is presented. METHODS: SSCs and milled allograft were impacted into necrotic bone in five femoral heads of four patients. Cell viability was confirmed by parallel in vitro culture of the cell-graft constructs. Patient follow-up was by serial clinical and radiological examination. Tissue engineered bone was retrieved from two retrieved femoral heads and was analysed by histology, microcomputed tomography (µCT) and mechanical testing. RESULTS: Three patients remain asymptomatic at 22- to 44-month follow-up. One patient (both hips) required total hip replacement due to widespread residual necrosis. Retrieved tissue engineered bone demonstrated a mature trabecular micro-architecture histologically and on µCT. Bone density and axial compression strength were comparable to trabecular bone. CONCLUSIONS: Clinical follow-up shows this to be an effective new treatment for focal early stage avascular necrosis of the femoral head. Unique retrieval analysis of clinically translated tissue engineered bone has demonstrated regeneration of tissue that is both structurally and functionally analogous to normal trabecular bone.

TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.

BACKGROUND AND AIMS: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. METHODS: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. RESULTS: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. CONCLUSIONS: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.

Body mass index and nutritional intake following Elexacaftor/Tezacaftor/Ivacaftor modulator therapy in adults with cystic fibrosis.

BACKGROUND: Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy is often associated with increased body mass index (BMI) in people with cystic fibrosis (CF). This is thought to reflect improved clinical stability and increased appetite and nutritional intake. We explored the change in BMI and nutritional intake following ETI modulator therapy in adults with CF. METHODS: Dietary intake, measured with myfood24®, and BMI were collected from adults with CF at baseline and follow-up as part of an observational study. Changes in BMI and nutritional intake in participants who commenced ETI therapy between time points were assessed. To contextualize findings, we also assessed changes in BMI and nutritional intake between study points in a group on no modulators. RESULTS: In the pre and post ETI threapy group (n = 40), BMI significantly increased from 23.0 kg/m2 (IQR 21.4, 25.3) at baseline to 24.6 kg/m2 (IQR 23.0, 26.7) at follow-up (p<0.001), with a median of 68 weeks between time points (range 20-94 weeks) and median duration of ETI therapy was 23 weeks (range 7-72 weeks). There was a significant decrease in energy intake from 2551 kcal/day (IQR 2107, 3115) to 2153 kcal/day (IQR 1648, 2606), p<0.001. In the no modulator group (n = 10), BMI and energy intake did not significantly change between time points (p>0.05), a median of 28 weeks apart (range 20-76 weeks). CONCLUSIONS: These findings tentatively suggest that the increase in BMI with ETI therapy may not simply be attributable to an increase in oral intake. Further exploration into the underlying aetiology of weight gain with ETI therapy is needed.

Diabetes is associated with increased burden of gastrointestinal symptoms in adults with cystic fibrosis.

BACKGROUND: Individuals with diabetes mellitus (DM) are known to frequently experience gastrointestinal (GI) symptoms. In contrast, the impact of cystic fibrosis-related diabetes (CFRD) on accentuating GI symptoms in people with cystic fibrosis (pwCF) is unknown. We sought to examine this. METHODS: Abdominal symptoms were measured using the validated CF-specific GI symptom questionnaire - CFAbd-Score© - as part of a multicentre cohort study in pancreatic insufficient adults with CF, not on cystic fibrosis transmembrane conductance regulator (CFTR) modulators. The CFAbd-Score total score (0-100pts), its 5 domains, alongside nine specific GI symptoms associated with DM, were compared between the CFRD and non-CFRD groups. RESULTS: 27 (31%) and 61 (69%) participants with CF were recruited in the CFRD and non-CFRD groups respectively. Total CFAbd-Score and the two domains: gastroesophageal reflux disease and disorders of appetite were significantly higher in the CFRD group compared to the non-CFRD group (p<0.05), with the mean total CFAbd-Score being 25.4 ± 2.5 and 18.4 ± 1.5 in the CFRD and non-CFRD groups respectively. Among the nine GI symptoms commonly reported as elevated in DM, bloating and nausea were significantly more common in individuals with CFRD compared to those without (p<0.05). CONCLUSIONS: Individuals with CFRD overall, have a higher GI symptom burden, according to CFAbd-Scores. Specifically, they experience significantly more bloating and nausea. Close monitoring and further research is needed to better understand and manage GI symptoms in this group.

Cystic fibrosis, primary ciliary dyskinesia and non-cystic fibrosis bronchiectasis: update 2008-11.

A review is presented of key clinical papers published in Thorax and elsewhere between 2008 and April 2011 which have advanced our understanding of cystic fibrosis (CF), primary ciliary dyskinesia and non-CF bronchiectasis. Studies were identified through searches of the Thorax archive and the Medline database. Within the field of CF, the following key themes were studied: diagnosis in equivocal CF, assessment of CF lung disease, novel therapies addressing the basic defect in CF, maintenance pulmonary therapies, management of early Pseudomonas infection, the microbiology of CF lung disease, renal impairment in CF and controversies in lung transplantation in CF.