Mechanisms affecting the implementation of a national antimicrobial stewardship programme; multi-professional perspectives explained using normalisation process theory.

Background: Antimicrobial stewardship (AMS) describes activities concerned with safe-guarding antibiotics for the future, reducing drivers for the major global public health threat of antimicrobial resistance (AMR), whereby antibiotics are less effective in preventing and treating infections. Appropriate antibiotic prescribing is central to AMS. Whilst previous studies have explored the effectiveness of specific AMS interventions, largely from uni-professional perspectives, our literature search could not find any existing evidence evaluating the processes of implementing an integrated national AMS programme from multi-professional perspectives. Methods: This study sought to explain mechanisms affecting the implementation of a national antimicrobial stewardship programme, from multi-professional perspectives. Data collection involved in-depth qualitative telephone interviews with 27 implementation lead clinicians from 14/15 Scottish Health Boards and 15 focus groups with doctors, nurses and clinical pharmacists (n = 72) from five Health Boards, purposively selected for reported prescribing variation. Data was first thematically analysed, barriers and enablers were then categorised, and Normalisation Process Theory (NPT) was used as an interpretive lens to explain mechanisms affecting the implementation process. Analysis addressed the NPT questions 'which group of actors have which problems, in which domains, and what sort of problems impact on the normalisation of AMS into everyday hospital practice'. Results: Results indicated that major barriers relate to organisational context and resource availability. AMS had coherence for implementation leads and prescribing doctors; less so for consultants and nurses who may not access training. Conflicting priorities made obtaining buy-in from some consultants difficult; limited role perceptions meant few nurses or clinical pharmacists engaged with AMS. Collective individual and team action to implement AMS could be constrained by lack of medical continuity and hierarchical relationships. Reflexive monitoring based on audit results was limited by the capacity of AMS Leads to provide direct feedback to practitioners. Conclusions: This study provides original evidence of barriers and enablers to the implementation of a national AMS programme, from multi-professional, multi-organisational perspectives. The use of a robust theoretical framework (NPT) added methodological rigour to the findings. Our results are of international significance to healthcare policy makers and practitioners seeking to strengthen the sustainable implementation of hospital AMS programmes in comparable contexts

Tools for the identification of bioactives impacting the metabolic syndrome: Screening of a botanical extract library using subcutaneous and visceral human adipose-derived stem cell-based assays

Plant extracts continue to represent an untapped source of renewable therapeutic compounds for the treatment and prevention of illnesses including chronic metabolic disorders. With the increase in worldwide obesity and its related morbidities, the need for identifying safe and effective treatments is also rising. As such, use of primary human adipose-derived stem cells represents a physiologically relevant cell system to screen for bioactive agents in the prevention and treatment of obesity and its related complications. By using these cells in a primary screen, the risk and cost of identifying artifacts due to interspecies variation and immortalized cell lines is eliminated. We demonstrate that these cells can be formatted into 384-well high throughput screens to rapidly identify botanical extracts that affect lipogenesis and lipolysis. Additionally, counterscreening with human primary stem cells from distinct adipose depots can be routinely performed to identify tissue specific responses. In our study, over 500 botanical extracts were screened and 16 (2.7%) were found to affect lipogenesis and 4 (0.7%) affected lipolysis. © 2012 Elsevier Inc

Advancing women in healthcare leadership : a systematic review and meta-synthesis of multi-sector evidence on organisational interventions

Women are underrepresented in healthcare leadership, yet evidence on impactful organisational strategies, practices and policies that advance women's careers are limited. We aimed to explore these across sectors to gain insight into measurably advancing women in leadership in healthcare. A systematic review was performed across Medline via OVID; Medline in-process and other non-indexed citations via OVID; PsycINFO and SCOPUS from January 2000 to March 2021. Methods are outlined in a published protocol registered on PROSPERO (CRD42020162115). Eligible studies reported on organisational interventions for advancing women in leadership with at least one measurable outcome. Studies were assessed independently by two reviewers. Identified interventions were organised into categories and meta-synthesis was completed following the 'ENhancing Transparency in REporting the synthesis of Qualitative research' (ENTREQ) statement. There were 91 eligible studies from 6 continents with 40 quantitative, 38 qualitative and 13 mixed methods studies. These spanned academia, health, government, sports, hospitality, finance and information technology sectors, with around half of studies in health and academia. Sample size, career stage and outcomes ranged broadly. Potentially effective interventions consistently reported that organisational leadership, commitment and accountability were key drivers of organisational change. Organisational intervention categories included i) organisational processes; ii) awareness and engagement; iii) mentoring and networking; iv) leadership development; and v) support tools. A descriptive meta-synthesis of detailed strategies, policies and practices within these categories was completed. This review provides an evidence base on organisational interventions for advancing women in leadership across diverse settings, with lessons for healthcare. It transcends the focus on the individual to target organisational change, capturing measurable change across intervention categories. This work directly informs a national initiative with international links, to enable women to achieve their career goals in healthcare and moves beyond the focus on barriers to solutions

2MASSJ035523.51+113337.4: A Young, Dusty, Nearby, Isolated Brown Dwarf Resembling A Giant Exoplanet

We present parallax and proper motion measurements, near-infrared spectra, and WISE photometry for the low surface gravity L5gamma dwarf 2MASSJ035523.37+113343.7 (2M0355). We use these data to evaluate photometric, spectral, and kinematic signatures of youth as 2M0355 is the reddest isolated L dwarf yet classified. We confirm its low-gravity spectral morphology and find a strong resemblance to the sharp triangular shaped $H$-band spectrum of the 10 Myr planetary-mass object 2M1207b. We find that 2M0355 is underluminous compared to a normal field L5 dwarf in the optical and MKO J,H, and K bands and transitions to being overluminous from 3-12 microns, indicating that enhanced photospheric dust shifts flux to longer wavelengths for young, low-gravity objects, creating a red spectral energy distribution. Investigating the near-infrared color magnitude diagram for brown dwarfs confirms that 2M0355 is redder and underluminous compared to the known brown dwarf population, similar to the peculiarities of directly imaged exoplanets 2M1207b and HR8799bcd. We calculate UVW space velocities and find that the motion of 2M0355 is consistent with young disk objects (< 2-3 Gyr) and it shows a high likelihood of membership in the AB Doradus association.Comment: 23 pages, 10 figures, 5 Tables, Submitted to AJ 13 May 201

Recommendations for determining HPV status in patients with oropharyngeal cancers under TNM8 guidelines : a two-tier approach

ACKNOWLEDGEMENTS The funders had no role in study design, collection, data analysis or interpretation of the data. This work received funding from the Medical Research Council (D.Mc.C. and J.J.), the Health and Social Care Research and Development Division of the Northern Ireland Public Health Agency (D.M.c.C., J.J., M.Mo.), the Wellcome Trust through the Wellcome-FDS Research Training Fellowship, the Faculty of Dental Surgery of the Royal College of Surgeons of England (A.G.S.) and GlaxoSmithKline Ltd (T.J.). The Northern Ireland OPSCC TMAs used in this research were received from the Northern Ireland Biobank which has received funds from Health and Social Care Research and Development Division of the Public Health Agency in Northern Ireland and the Friends of the Cancer Centre. The Northern Ireland Cancer Registry who receives funding from the Northern Ireland Public Health Agency carried out collection of clinical data for the Northern Ireland OPSCC patients. The Faculty of Dental Surgery of the Royal College of Surgeons of England and the Liverpool Bio-innovation Hub Biobank carried out collection of clinical data for the Liverpool OPSCC patients.Peer reviewedPublisher PD

Surveying Nearby Brown Dwarfs with HGCA: Direct Imaging Discovery of a Faint, High-Mass Brown Dwarf Orbiting HD 176535 A

Brown dwarfs with well-measured masses, ages and luminosities provide direct benchmark tests of substellar formation and evolutionary models. We report the first results from a direct imaging survey aiming to find and characterize substellar companions to nearby accelerating stars with the assistance of the Hipparcos-Gaia Catalog of Accelerations (HGCA). In this paper, we present a joint high-contrast imaging and astrometric discovery of a substellar companion to HD 176535 A, a K3.5V main-sequence star aged approximately $3.59_{-1.15}^{+0.87}$ Gyrs at a distance of $36.99 \pm 0.03$ pc. In advance of our high-contrast imaging observations, we combined precision HARPS RVs and HGCA astrometry to predict the potential companion's location and mass. We thereafter acquired two nights of KeckAO/NIRC2 direct imaging observations in the $L'$ band, which revealed a companion with a contrast of $\Delta L'_p = 9.20\pm0.06$ mag at a projected separation of $\approx$0.\!\!''35 ($\approx$13 AU) from the host star. We revise our orbital fit by incorporating our dual-epoch relative astrometry using the open-source MCMC orbit fitting code $\tt orvara$. HD 176535 B is a new benchmark dwarf useful for constraining the evolutionary and atmospheric models of high-mass brown dwarfs. We found a luminosity of $\rm log(L_{bol}/L_{\odot}) = -5.26\pm0.06$ and a model-dependent effective temperature of $980 \pm 35$ K for HD 176535 B. Our dynamical mass suggests that some substellar evolutionary models may be underestimating luminosity for high-mass T dwarfs. Given its angular separation and luminosity, HD 176535 B would make a promising candidate for Aperture Masking Interferometry with JWST and GRAVITY/KPIC, and further spectroscopic characterization with instruments like the CHARIS/SCExAO/Subaru integral field spectrograph

A multi-decade record of high quality fCO2 data in version 3 of the Surface Ocean CO2 Atlas (SOCAT)

The Surface Ocean CO2 Atlas (SOCAT) is a synthesis of quality-controlled fCO2 (fugacity of carbon dioxide) values for the global surface oceans and coastal seas with regular updates. Version 3 of SOCAT has 14.7 million fCO2 values from 3646 data sets covering the years 1957 to 2014. This latest version has an additional 4.6 million fCO2 values relative to version 2 and extends the record from 2011 to 2014. Version 3 also significantly increases the data availability for 2005 to 2013. SOCAT has an average of approximately 1.2 million surface water fCO2 values per year for the years 2006 to 2012. Quality and documentation of the data has improved. A new feature is the data set quality control (QC) flag of E for data from alternative sensors and platforms. The accuracy of surface water fCO2 has been defined for all data set QC flags. Automated range checking has been carried out for all data sets during their upload into SOCAT. The upgrade of the interactive Data Set Viewer (previously known as the Cruise Data Viewer) allows better interrogation of the SOCAT data collection and rapid creation of high-quality figures for scientific presentations. Automated data upload has been launched for version 4 and will enable more frequent SOCAT releases in the future. High-profile scientific applications of SOCAT include quantification of the ocean sink for atmospheric carbon dioxide and its long-term variation, detection of ocean acidification, as well as evaluation of coupled-climate and ocean-only biogeochemical models. Users of SOCAT data products are urged to acknowledge the contribution of data providers, as stated in the SOCAT Fair Data Use Statement. This ESSD (Earth System Science Data) “living data” publication documents the methods and data sets used for the assembly of this new version of the SOCAT data collection and compares these with those used for earlier versions of the data collection (Pfeil et al., 2013; Sabine et al., 2013; Bakker et al., 2014). Individual data set files, included in the synthesis product, can be downloaded here: doi:10.1594/PANGAEA.849770. The gridded products are available here: doi:10.3334/CDIAC/OTG.SOCAT_V3_GRID

Amplification and demultiplexing in insulin-regulated Akt protein kinase pathway in adipocytes.

Akt plays a major role in insulin regulation of metabolism in muscle, fat, and liver. Here, we show that in 3T3-L1 adipocytes, Akt operates optimally over a limited dynamic range. This indicates that Akt is a highly sensitive amplification step in the pathway. With robust insulin stimulation, substantial changes in Akt phosphorylation using either pharmacologic or genetic manipulations had relatively little effect on Akt activity. By integrating these data we observed that half-maximal Akt activity was achieved at a threshold level of Akt phosphorylation corresponding to 5-22% of its full dynamic range. This behavior was also associated with lack of concordance or demultiplexing in the behavior of downstream components. Most notably, FoxO1 phosphorylation was more sensitive to insulin and did not exhibit a change in its rate of phosphorylation between 1 and 100 nm insulin compared with other substrates (AS160, TSC2, GSK3). Similar differences were observed between various insulin-regulated pathways such as GLUT4 translocation and protein synthesis. These data indicate that Akt itself is a major amplification switch in the insulin signaling pathway and that features of the pathway enable the insulin signal to be split or demultiplexed into discrete outputs. This has important implications for the role of this pathway in disease

Serum brain-derived neurotrophic factor: Determinants and relationship with depressive symptoms in a community population of middle-aged and elderly people

OBJECTIVES: Brain-derived neurotrophic factor (BDNF) is involved in major depressive disorder and neurodegenerative diseases. Clinical studies, showing decreased serum BDNF levels, are difficult to interpret due to limited knowledge of potential confounders and mixed results for age and sex effects. We explored potential determinants of serum BDNF levels in a community sample of 1230 subjects. METHODS: Multiple linear regression analyses with serum BDNF level as the dependent variable were conducted to explore the effect of four categories of potential BDNF determinants (sampling characteristics, sociodemographic variables, lifestyle factors and somatic diseases) and of self-reported depressive symptoms (Beck's Depression Inventory (BDI). RESULTS: Our results show that BDNF levels decline with age in women, whereas in men levels remain stable. Moreover, after controlling for age and gender, the assays still showed lower serum BDNF levels with higher BDI sum scores. Effects remained significant after correction for two main confounders (time of sampling and smoking), suggesting that they serve as molecular trait factors independent of lifestyle factors. CONCLUSIONS: Given the age-sex interaction on serum BDNF levels and the known association between BDNF and gonadal hormones, research is warranted to delineate the effects of the latter interaction on the risk of psychiatric and neurodegenerative diseases

The JWST Early Release Science Program for Direct Observations of Exoplanetary Systems II: A 1 to 20 Micron Spectrum of the Planetary-Mass Companion VHS 1256-1257 b

We present the highest fidelity spectrum to date of a planetary-mass object. VHS 1256 b is a $<$20 M$_\mathrm{Jup}$ widely separated ($\sim$8\arcsec, a = 150 au), young, planetary-mass companion that shares photometric colors and spectroscopic features with the directly imaged exoplanets HR 8799 c, d, and e. As an L-to-T transition object, VHS 1256 b exists along the region of the color-magnitude diagram where substellar atmospheres transition from cloudy to clear. We observed VHS 1256~b with \textit{JWST}'s NIRSpec IFU and MIRI MRS modes for coverage from 1 $\mu$m to 20 $\mu$m at resolutions of $\sim$1,000 - 3,700. Water, methane, carbon monoxide, carbon dioxide, sodium, and potassium are observed in several portions of the \textit{JWST} spectrum based on comparisons from template brown dwarf spectra, molecular opacities, and atmospheric models. The spectral shape of VHS 1256 b is influenced by disequilibrium chemistry and clouds. We directly detect silicate clouds, the first such detection reported for a planetary-mass companion.Comment: Accepted ApJL Iterations of spectra reduced by the ERS team are hosted at this link: https://github.com/bemiles/JWST_VHS1256b_Reduction/tree/main/reduced_spectr