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.

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.

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.

Prebiotic oligosaccharides in early life alter gut microbiome development in male mice while supporting influenza vaccination responses.

Beneficial modulation of the gut microbiota is an attractive therapeutic approach to improve the efficacy of vaccine-induced immunity. In this study, mice were supplemented with the prebiotic milk oligosaccharide 2'-fucosyllactose (2'FL) as well as a complex mixture of immune modulatory prebiotic short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS) from different stages in early life. Adult mice were vaccinated with trivalent influenza vaccine (TIV) and both development of the gut microbiota and antibody-mediated vaccine responses were followed over time. Within the control group, female mice demonstrated a larger antibody response to TIV vaccination than male mice, which was accompanied by enhanced cytokine production by splenocytes and a higher percentage of plasma cells in skin draining lymph nodes. In addition, the prebiotic diet improved vaccine-specific antibody responses in male mice. Introduction of prebiotics into the diet modulated the gut microbiota composition and at the genus level several bacterial groups showed a significant interaction effect which potentially contributed to the immunological effects observed. This study provides insight in the effect of scGOS/lcFOS/2'FL in influenza vaccination antibody production.

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.

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.

Outcomes Following Bronchial Artery Embolisation for Haemoptysis in Cystic Fibrosis.

BACKGROUND: Bronchial artery embolisation (BAE) is recommended for the treatment of massive haemoptysis in cystic fibrosis (CF), but there are no randomised controlled trials of this therapy and its role in sub-massive haemoptysis is unclear. This study aimed to determine the outcomes and safety of BAE in adults with CF. MATERIALS AND METHODS: All patients with CF undergoing BAE at our centre between March 2011 and January 2015 were identified at the time of the procedure. Patient records were reviewed at hospital discharge, death or one month post-procedure (whichever was soonest). Follow-up continued to January 2016. Severity of haemoptysis was classified as: massive (>240 ml/24 h or >100 ml/day for ≥2 days), moderate-severe (>20 ml/24 h) or mild (<20 ml/24 h). RESULTS: Twenty-seven patients underwent 51 BAE procedures over a median follow-up period of 26 months (range 1-54). Ten patients (37%) required more than one BAE during the study. BAE was performed for massive haemoptysis in 18 cases (35%). Haemoptysis recurred after 31 (61%) of BAE procedures with no difference in recurrence rates between massive and sub-massive haemoptysis. Side effects were reported after 61% of procedures with chest pain the most common adverse event . Mortality after first BAE in the study was 3.9% at 30 days and 14.8% at 12 months. No significant predictors of mortality were identified. CONCLUSIONS: BAE is often effective in controlling haemoptysis but is associated with considerable morbidity and high recurrence rates.

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.

The clinical significance and impact of interleukin 15 on keratinocyte cell growth and migration.

Chronic wounds represent a significant burden to health services and are associated with patient morbidity. Novel methods to diagnose and/or treat problematic wounds are needed. Interleukin (IL)-15 is a cytokine involved in a number of biological processes and disease states such as inflammation, healing and cancer progression. The current study explores the expression profile of IL-15 and IL-15 receptor α (IL-15Rα) in chronic wounds and its impact on keratinocytes. IL-15 and IL-15Rα expression were examined in healing and non-healing chronic wounds using qPCR and immunohistochemical analysis. The impact of recombinant IL-15 (rhIL-15) on human adult low calcium temperature (HaCaT) keratinocyte growth and migratory potential was further examined. IL-15 transcript expression was slightly, though non-significantly elevated in healing chronic wounds compared with non-healing chronic wounds. IL-15 protein staining was minimal in both subtypes of chronic wounds. By contrast, IL-15Rα transcript and protein expression were both observed to be enhanced in non-healing chronic wounds compared with healing chronic wounds. The treatment of HaCaT cells with rhIL-15 generally enhanced cell growth and promoted migration. Analysis with small molecule inhibitors suggested that the pro-migratory effect of rhIL-15 may be associated with ERK, AKT, PLCγ and FAK signalling. IL-15 may promote healing traits in keratinocytes and the differential expression of IL-15Rα is observed in chronic wounds. Together, this may imply a complex role for this interleukin in wound healing.

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.

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.

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.

Protoplast-to-plant regeneration of American elm (Ulmus americana).

This study describes a protocol for regeneration of plants from cell suspension-derived protoplasts of American elm (Ulmus americana). Efficient protoplast isolation was achieved from a two-phase culture system through the incorporation of 100 µM 2-aminoindan-2-phosphonic acid, with a yield of approximately 2 × 10(6) protoplasts/ml packed cell volume. Isolated protoplasts failed to survive in liquid or alginate bead culture systems but initiated and continued to divide when embedded in low melting point agarose beads. Protoplast-derived callus proliferated and differentiated into shoot buds in response to 10 or 20 µM thidiazuron. Differentiated buds elongated and continued to proliferate on elm shoot medium supplemented with 3.0 µM GA3. The protoplast-derived shoots rooted and acclimatized to greenhouse conditions and continued to grow. This system provides the first protoplast-to-plant regeneration system for American elm and provides a framework for the development of protoplast fusion or genome editing technologies.