Top research priorities in liver and gallbladder disorders in the UK

OBJECTIVES: There is a mismatch between research questions considered important by patients, carers and healthcare professionals and the research performed in many fields of medicine. The non-alcohol-related liver and gallbladder disorders priority setting partnership was established to identify the top research priorities in the prevention, diagnostic and treatment of gallbladder disorders and liver disorders not covered by the James-Lind Alliance (JLA) alcohol-related liver disease priority setting partnership. DESIGN: The methods broadly followed the principles of the JLA guidebook. The one major deviation from the JLA methodology was the final step of identifying priorities: instead of prioritisation by group discussions at a consensus workshop involving stakeholders, the prioritisation was achieved by a modified Delphi consensus process. RESULTS: A total of 428 unique valid diagnostic or treatment research questions were identified. A literature review established that none of these questions were considered 'answered' that is, high-quality systematic reviews suggest that further research is not required on the topic. The Delphi panel achieved consensus (at least 80% Delphi panel members agreed) that a research question was a top research priority for six questions. Four additional research questions with highest proportion of Delphi panel members ranking the question as highly important were added to constitute the top 10 research priorities. CONCLUSIONS: A priority setting process involving patients, carers and healthcare professionals has been used to identify the top 10priority areas for research related to liver and gallbladder disorders. Basic, translational, clinical and public health research are required to address these uncertainties

Comparative Genomics of Gardnerella vaginalis Strains Reveals Substantial Differences in Metabolic and Virulence Potential

Gardnerella vaginalis is described as a common vaginal bacterial species whose presence correlates strongly with bacterial vaginosis (BV). Here we report the genome sequencing and comparative analyses of three strains of G. vaginalis. Strains 317 (ATCC 14019) and 594 (ATCC 14018) were isolated from the vaginal tracts of women with symptomatic BV, while Strain 409-05 was isolated from a healthy, asymptomatic individual with a Nugent score of 9.Substantial genomic rearrangement and heterogeneity were observed that appeared to have resulted from both mobile elements and substantial lateral gene transfer. These genomic differences translated to differences in metabolic potential. All strains are equipped with significant virulence potential, including genes encoding the previously described vaginolysin, pili for cytoadhesion, EPS biosynthetic genes for biofilm formation, and antimicrobial resistance systems, We also observed systems promoting multi-drug and lantibiotic extrusion. All G. vaginalis strains possess a large number of genes that may enhance their ability to compete with and exclude other vaginal colonists. These include up to six toxin-antitoxin systems and up to nine additional antitoxins lacking cognate toxins, several of which are clustered within each genome. All strains encode bacteriocidal toxins, including two lysozyme-like toxins produced uniquely by strain 409-05. Interestingly, the BV isolates encode numerous proteins not found in strain 409-05 that likely increase their pathogenic potential. These include enzymes enabling mucin degradation, a trait previously described to strongly correlate with BV, although commonly attributed to non-G. vaginalis species.Collectively, our results indicate that all three strains are able to thrive in vaginal environments, and therein the BV isolates are capable of occupying a niche that is unique from 409-05. Each strain has significant virulence potential, although genomic and metabolic differences, such as the ability to degrade mucin, indicate that the detection of G. vaginalis in the vaginal tract provides only partial information on the physiological potential of the organism

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Premium offerings in the sharing economy: Authentic immersions

Over the past few years the sharing economy has grown tremendously, driven in part by traveler desires for authentic and unique experiences. In response to these modern changes, peer-to-peer (P2P) marketplaces (e.g., Airbnb) are seeking additional revenue streams, expanding beyond room rentals into guided tours, recreational, and cultural experiences. Rather than act solely as sharing economy lodging establishments, in the near future providers will increasingly supply authentic and immersive vacation experiences, acting as a host, guide, concierge, and traveling companion to their guests. This paper explores the ability of P2P providers to command premium pricing for authentic and immersive P2P offerings. The paper details this possibility, listing drivers of change before positing a scenario that helps envision a future in which P2P providers seize this opportunity. Finally, the paper closes with limitations, practical implications, and future research recommendations

Expression of the beta-2 adrenergic receptor (ADRB-2) in human and monkey ovarian follicles: a marker of growing follicles?

Background ADRB-2 was implicated in rodent ovarian functions, including initial follicular growth. In contrast, ADRB-2 expression and function in nonhuman primate and human ovary were not fully known but innervation and significant levels of norepinephrine (NE), which is a ligand at the ADRB-2, were reported in the ovary. Methods We studied expression of ADRB-2 in human and rhesus monkey ovary (RT-PCR, immunohistochemistry; laser micro dissection) and measured levels of norepinephrine (NE; ELISA) in monkey follicular fluid (FF). 3D cultures of monkey follicles (4 animals) were exposed to NE or the ADRB-2 agonist isoproterenol (ISO), and follicular development (size) was monitored. Upon termination expression of ADRB-2, FSH receptor and aromatase genes were examined. Results Immunohistochemistry and RT-PCR of either human follicular granulosa cells (GCs) obtained by laser micro dissection or isolated monkey follicles revealed ADRB-2 in GCs of primordial, primary, secondary and tertiary follicles. Staining of GCs in primordial and primary follicles was intense. In large preantral and antral follicles the staining was heterogeneous, with positive and negative GCs present but GCs lining the antrum of large follicles were generally strongly immunopositive. Theca, interstitial, and ovarian surface epithelial cells were also positive. NE was detected in FF of preovulatory antral monkey follicles (0.37 + 0.05 ng/ml; n = 7; ELISA) but not in serum. We examined preantral follicles ranging from 152 to 366 μm in diameter in a 3D culture in media supplemented with follicle stimulating hormone (FSH). Under these conditions, neither NE, nor ISO, influenced growth rate in a period lasting up to one month. Upon termination of the cultures, all surviving follicles expressed aromatase and FSH receptors, but only about half of them also co-expressed ADRB-2. The ADRB-2 expression was not correlated with the treatment but was positively correlated with the follicular size at the beginning and at the end of the culture period. Hence, expression of ADRB-2 was found in the largest and fastest-in vitro growing follicles. Conclusions The results imply ADRB-2-mediated actions in the development of primate follicles. Drugs interfering with ADRB-2 are used to treat medical conditions and may have unexplored effects in the human ovary

The temporal evolution of electron distributions and associated wave activity following substorm injections in the inner magnetosphere

The temporal evolution of electron distributions and associated wave activity following substorm injections in the inner magnetosphere are investigated using data from the CRRES satellite. Equatorial electron distributions and concomitant wave spectra outside the plasmapause on the nightside of the Earth are studied as a function of time since injection determined from the auroral-electrojet index (AE). The electron cyclotron harmonic (ECH) wave amplitudes are shown to be very sensitive to small modeling errors in the location of the magnetic equator. They are best understood at the ECH equator, defined by the local, maximum in the ECH wave activity in the vicinity of the nominal magnetic equator, suggesting that the ECH equator is a better measure of the location of the true equator. Strong ECH and whistler mode wave amplitudes are associated with the injected distributions and at the ECH equator, in the region 6.0 less than or equal to L < 7.0, exponential fits reveal wave amplitude decay time constants of 6.3+/-1.2 and 4.6+/-0.7 hours, respectively. Pancake electron distributions are seen to develop from injected distributions that are nearly isotropic in velocity space and, in this region, are seen to form on a similar timescale of approximately 4 hours suggesting that both wave types are involved in their production. The timescale for pancake production and wave decay is comparable with the average time interval between substorm events so that the wave-particle interactions are almost continually present in this region leading to a continual supply of electrons to power the diffuse aurora. In the region 3.8 less than or equal to L < 6.0 the timescale for wave decay at the ECH equator is 2.3 +/- 0.6 and 1.1 +/- 0.2 hours for ECH waves and whistler mode waves respectively, although the pancakes in this region show no clear evolution as a function of time

The Asia-Pacific tourism workforce of the future : using Delphi techniques to identify possible scenarios

This article addresses the challenges of long-term planning for a tourism workforce at a regional level, a significant yet underconceptualized area in the literature. We draw on Yeoman's future thinking techniques to generate a four-quadrant matrix designed to facilitate the development of scenarios that identify workforce challenges the tourism sector in the Asia- Pacific is likely to face through to 2030. Applying a modified Delphi technique, an expert panel aided in the formulation of dimensions on which our matrix is based. Their inputs over three rounds informed the development of four scenarios for the future of the tourism workforce in the Asia-Pacific. Utilizing these scenarios or "possibility spaces," the article provides a framework for discussion and a platform for workforce planning and policy within this region