Exploring the natural history of intrinsic capacity impairments: longitudinal patterns in the 10/66 study

Backgroundintrinsic capacity (IC) is a construct encompassing people’s physical and mental abilities. There is an implicit link amongst IC domains: cognition, locomotion, nutrition, sensory and psychological. However, little is known about the integration of the domains.Objectivesto investigate patterns in the presentation and evolution of IC domain impairments in low-and-middle-income countries and if such patterns were associated with adverse outcomes.Methodssecondary analyses of the first two waves of the 10/66 study (population-based surveys conducted in eight urban and four rural catchment areas in Cuba, Dominican Republic, Puerto Rico, Venezuela, Peru, Mexico and China). We applied latent transition analysis on IC to find latent statuses (latent clusters) of IC domain impairments. We evaluated the longitudinal association of the latent statuses with the risk of frailty, disability and mortality, and tested concurrent and predictive validity.Resultsamongst 14,923 participants included, the four latent statuses were: high IC (43%), low deterioration with impaired locomotion (17%), high deterioration without cognitive impairment (22%), and high deterioration with cognitive impairment (18%). A total of 61% of the participants worsened over time, 35% were stable, and 3% improved to a healthier status.Participants with deteriorated IC had a significantly higher risk of frailty, disability and dementia than people with high IC. There was strong concurrent and predictive validity. (Mortality Hazard Ratio = 4.60, 95%CI 4.16; 5.09; Harrel’s C = 0.73 (95%CI 0.72;0.74)).Conclusionshalf of the study population had high IC at baseline, and most participants followed a worsening trend. Four qualitatively different IC statuses or statuses were characterised by low and high levels of deterioration associated with their risk of disability and frailty. Locomotion and cognition impairments showed other trends than psychological and nutrition domains across the latent statuses

UK Healthcare Workers' Experiences of Major System Change in Elective Surgery During the COVID-19 Pandemic: Reflections on Rapid Service Adaptation

Background: The coronavirus disease 2019 (COVID-19) pandemic disrupted the delivery of elective surgery in the United Kingdom. The majority of planned surgery was cancelled or postponed in March 2020 for the duration of the first wave of the pandemic. We investigated the experiences of staff responsible for delivering rapid changes to surgical services during the first wave of the pandemic in the United Kingdom, with the aim of developing lessons for future major systems change (MSC). Methods: Using a rapid qualitative study design, we conducted 25 interviews with frontline surgical staff during the first wave of the pandemic. Framework analysis was used to organise and interpret findings. Results: Staff discussed positive and negative experiences of rapid service organisation. Clinician-led decision-making, the flexibility of individual staff and teams, and the opportunity to innovate service design were all seen as positive contributors to success in service adaptation. The negative aspects of rapid change were inconsistent guidance from national government and medical bodies, top-down decisions about when to cancel and restart surgery, the challenges of delivering emergency surgical care safely and the complexity of prioritising surgical cases when services re-started. Conclusion: Success in the rapid reorganisation of elective surgical services can be attributed to the flexibility and adaptability of staff. However, there was an absence of involvement of staff in wider system-level pandemic decisionmaking and competing guidance from national bodies. Involving staff in decisions about the organisation and delivery of MSC is essential for the sustainability of change processes

Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells

Despite major therapeutic advances leading to improved patient outcomes for other haematological malignancies, development of new therapeutics to improve prognosis for acute myeloid leukemia (AML) patients remains an area of unmet clinical need. Overexpression of GATA2, a member of the GATA family of zinc finger transcription factors, has been implicated in AML. In settings where GATA2 is overexpressed in human AML cells, K7174, a proteasome inhibitor that inhibits GATA2, induces apoptosis and enhances the killing activity of AML chemotherapeutics in vitro yet targeting the proteasome has been associated with high toxicity in the clinic. Using an in silico approach, we embarked on a screen to identify specific GATA2 inhibitors that will target AML cells independently of the proteasome. A shape-based virtual screening of an in-house library of small molecules was performed using a low-energy conformation of K7174. The virtual hit compounds were subsequently filtered according to their potential selectivity for GATA2 over the proteasome. From 15 selected compounds evaluated for their ability to kill AML cells in vitro, one compound, an asymmetrical substituted piperazine with Hepatitis C antiviral activity, exhibited superior ability to induce apoptosis and reduce cell cycling in AML cells without proteasome inhibition. This compound was also able to promote cell death of the relapse propagating leukemic stem cell (LSC) compartment while sparing Gata2 knockout LSCs, crucially demonstrating specificity to inhibit GATA2. We have identified a GATA2 specific inhibitor with promising capability to target AML cells in vitro, including LSCs that underpin poor prognosis in AML

Larval Development in Tropical Gar (Atractosteus tropicus) Is Dependent on the Embryonic Thermal Regime: Ecological Implications under a Climate Change Context

In ectotherm species, environmental temperature plays a key role in development, growth, and survival. Thus, determining how temperature affects fish populations is of utmost importance to accurately predict the risk of climate change over fisheries and aquaculture, critical to warrant nutrition and food security in the coming years. Here, the potential effects of abnormal thermal regimes (24, 28 and 32 C; TR24, TR28, and TR32, respectively) exclusively applied during embryogenesis in tropical gar (Atractosteus tropicus) has been explored to decipher the potential consequences on hatching and growth from fertilization to 16 days post-fertilization (dpf), while effects on skeletal development and body morphology were explored at fertilization and 16 dpf. Egg incubation at higher temperatures induced an early hatching and mouth opening. A higher hatching rate was obtained in eggs incubated at 28 C when compared to those at 24 C. No differences were found in fish survival at 16 dpf, with values ranging from 84.89 to 88.86%, but increased wet body weight and standard length were found in larvae from TR24 and TR32 groups. Thermal regime during embryogenesis also altered the rate at which the skeletal development occurs. Larvae from the TR32 group showed an advanced skeletal development, with a higher development of cartilaginous structures at hatching but reduced at 16 dpf when compared with the TR24 and TR28 groups. Furthermore, this advanced skeletal development seemed to determine the fish body morphology. Based on biometric measures, a principal component analysis showed how along development, larvae from each thermal regime were clustered together, but with each population remaining clearly separated from each other. The current study shows how changes in temperature may induce craniofacial and morphological alterations in fish during early stages and contribute to understanding the possible effects of global warming in early development of fish and its ecological implications.Versión del edito

The 2HWC HAWC Observatory Gamma Ray Catalog

We present the first catalog of TeV gamma-ray sources realized with the recently completed High Altitude Water Cherenkov Observatory (HAWC). It is the most sensitive wide field-of-view TeV telescope currently in operation, with a 1-year survey sensitivity of ~5-10% of the flux of the Crab Nebula. With an instantaneous field of view >1.5 sr and >90% duty cycle, it continuously surveys and monitors the sky for gamma ray energies between hundreds GeV and tens of TeV. HAWC is located in Mexico at a latitude of 19 degree North and was completed in March 2015. Here, we present the 2HWC catalog, which is the result of the first source search realized with the complete HAWC detector. Realized with 507 days of data and represents the most sensitive TeV survey to date for such a large fraction of the sky. A total of 39 sources were detected, with an expected contamination of 0.5 due to background fluctuation. Out of these sources, 16 are more than one degree away from any previously reported TeV source. The source list, including the position measurement, spectrum measurement, and uncertainties, is reported. Seven of the detected sources may be associated with pulsar wind nebulae, two with supernova remnants, two with blazars, and the remaining 23 have no firm identification yet.Comment: Submitted 2017/02/09 to the Astrophysical Journa

Perceptions and experiences of healthcare workers during the COVID-19 pandemic in the UK

OBJECTIVE: The COVID-19 pandemic has set unprecedented demand on the healthcare workforce around the world. The UK has been one of the most affected countries in Europe. The aim of this study was to explore the perceptions and experiences of healthcare workers (HCWs) in relation to COVID-19 and care delivery models implemented to deal with the pandemic in the UK. METHODS: The study was designed as a rapid appraisal combining: (1) a review of UK healthcare policies (n=35 policies), (2) mass media and social media analysis of front-line staff experiences and perceptions (n=101 newspaper articles, n=1 46 000 posts) and (3) in-depth (telephone) interviews with front-line staff (n=30 interviews). The findings from all streams were analysed using framework analysis. RESULTS: Limited personal protective equipment (PPE) and lack of routine testing created anxiety and distress and had a tangible impact on the workforce. When PPE was available, incorrect size and overheating complicated routine work. Lack of training for redeployed staff and the failure to consider the skills of redeployed staff for new areas were identified as problems. Positive aspects of daily work reported by HCWs included solidarity between colleagues, the establishment of well-being support structures and feeling valued by society. CONCLUSION: Our study highlighted the importance of taking into consideration the experiences and concerns of front-line staff during a pandemic. Staff working in the UK during the COVID-19 pandemic advocated clear and consistent guidelines, streamlined testing of HCWs, administration of PPE and acknowledgement of the effects of PPE on routine practice

Perceptions and experiences of healthcare workers during the COVID-19 pandemic in the UK

Objective The COVID-19 pandemic has set unprecedented demand on the healthcare workforce around the world. The UK has been one of the most affected countries in Europe. The aim of this study was to explore the perceptions and experiences of healthcare workers (HCWs) in relation to COVID-19 and care delivery models implemented to deal with the pandemic in the UK. Methods The study was designed as a rapid appraisal combining: (1) a review of UK healthcare policies (n=35 policies), (2) mass media and social media analysis of front-line staff experiences and perceptions (n=101 newspaper articles, n=1 46 000 posts) and (3) in-depth (telephone) interviews with front-line staff (n=30 interviews). The findings from all streams were analysed using framework analysis. Results Limited personal protective equipment (PPE) and lack of routine testing created anxiety and distress and had a tangible impact on the workforce. When PPE was available, incorrect size and overheating complicated routine work. Lack of training for redeployed staff and the failure to consider the skills of redeployed staff for new areas were identified as problems. Positive aspects of daily work reported by HCWs included solidarity between colleagues, the establishment of well-being support structures and feeling valued by society. Conclusion Our study highlighted the importance of taking into consideration the experiences and concerns of front-line staff during a pandemic. Staff working in the UK during the COVID-19 pandemic advocated clear and consistent guidelines, streamlined testing of HCWs, administration of PPE and acknowledgement of the effects of PPE on routine practice

The Sensitivity of HAWC to High-Mass Dark Matter Annihilations

The High Altitude Water Cherenkov (HAWC) observatory is a wide field-of-view detector sensitive to gamma rays of 100 GeV to a few hundred TeV. Located in central Mexico at 19 degrees North latitude and 4100 m above sea level, HAWC will observe gamma rays and cosmic rays with an array of water Cherenkov detectors. The full HAWC array is scheduled to be operational in Spring 2015. In this paper, we study the HAWC sensitivity to the gamma-ray signatures of high-mass (multi- TeV) dark matter annihilation. The HAWC observatory will be sensitive to diverse searches for dark matter annihilation, including annihilation from extended dark matter sources, the diffuse gamma-ray emission from dark matter annihilation, and gamma-ray emission from non-luminous dark matter subhalos. Here we consider the HAWC sensitivity to a subset of these sources, including dwarf galaxies, the M31 galaxy, the Virgo cluster, and the Galactic center. We simulate the HAWC response to gamma rays from these sources in several well-motivated dark matter annihilation channels. If no gamma-ray excess is observed, we show the limits HAWC can place on the dark matter cross-section from these sources. In particular, in the case of dark matter annihilation into gauge bosons, HAWC will be able to detect a narrow range of dark matter masses to cross-sections below thermal. HAWC should also be sensitive to non-thermal cross-sections for masses up to nearly 1000 TeV. The constraints placed by HAWC on the dark matter cross-section from known sources should be competitive with current limits in the mass range where HAWC has similar sensitivity. HAWC can additionally explore higher dark matter masses than are currently constrained.Comment: 15 pages, 4 figures, version to be published in PR

Conservation of the endemic dwarf carnivores of Cozumel Island, Mexico.

Cozumel Island, Mexico, harbours two endemic species of dwarf procyonids: the Pygmy Raccoon Procyon pygmaeus and the Dwarf Coati Nasua nelsoni. Both species are Critically Endangered, and are among the world&rsquo;s most threatened Carnivora. Here we summarise the research we have been conducting on their ecology, evolution, genetics, and conservation. We also summarise the conservation initiatives we have been undertaking and promoting in order to advance the conservation of these unique species and their habitats. This effort illustrates the importance of an interdisciplinary approach in conservation science and action in maximising effectiveness. Nevertheless, the precarious status of the species make it imperative to continue and expand the work we have carried out in Cozumel to prevent two imminent global extinctions.<br /

Daily monitoring of TeV gamma-ray emission from Mrk 421, Mrk 501, and the Crab Nebula with HAWC

We present results from daily monitoring of gamma rays in the energy range $\sim0.5$ to $\sim100$ TeV with the first 17 months of data from the High Altitude Water Cherenkov (HAWC) Observatory. Its wide field of view of 2 steradians and duty cycle of $>95$% are unique features compared to other TeV observatories that allow us to observe every source that transits over HAWC for up to $\sim6$ hours each sidereal day. This regular sampling yields unprecedented light curves from unbiased measurements that are independent of seasons or weather conditions. For the Crab Nebula as a reference source we find no variability in the TeV band. Our main focus is the study of the TeV blazars Markarian (Mrk) 421 and Mrk 501. A spectral fit for Mrk 421 yields a power law index $\Gamma=2.21 \pm0.14_{\mathrm{stat}}\pm0.20_{\mathrm{sys}}$ and an exponential cut-off $E_0=5.4 \pm 1.1_{\mathrm{stat}}\pm 1.0_{\mathrm{sys}}$ TeV. For Mrk 501, we find an index $\Gamma=1.60\pm 0.30_{\mathrm{stat}} \pm 0.20_{\mathrm{sys}}$ and exponential cut-off $E_0=5.7\pm 1.6_{\mathrm{stat}} \pm 1.0_{\mathrm{sys}}$ TeV. The light curves for both sources show clear variability and a Bayesian analysis is applied to identify changes between flux states. The highest per-transit fluxes observed from Mrk 421 exceed the Crab Nebula flux by a factor of approximately five. For Mrk 501, several transits show fluxes in excess of three times the Crab Nebula flux. In a comparison to lower energy gamma-ray and X-ray monitoring data with comparable sampling we cannot identify clear counterparts for the most significant flaring features observed by HAWC.Comment: 18 pages, 10 figures, accepted for publication in The Astrophysical Journa