Establishing key criteria to define and compare models of specialist palliative care : a mixed-methods study using qualitative interviews and Delphi survey

Background: Specialist palliative care services have various configurations of staff, processes and interventions, which determine how care is delivered. Currently, there is no consistent way to define and distinguish these different models of care. Aim: To identify the core components that characterise and differentiate existing models of specialist palliative care in the United Kingdom. Design: Mixed-methods study: (1) semi-structured interviews to identify criteria, (2) two-round Delphi study to rank/refine criteria, and (3) structured interviews to test/refine criteria. Setting/participants: Specialist palliative care stakeholders from hospice inpatient, hospital advisory, and community settings. Results: (1) Semi-structured interviews with 14 clinical leads, from eight UK organisations (five hospice inpatient units, two hospital advisory teams, five community teams), provided 34 preliminary criteria. (2) Delphi study: Round 1 (54 participants): thirty-four criteria presented, seven removed and seven added. Round 2 (30 participants): these 34 criteria were ranked with the 15 highest ranked criteria, including setting, type of care, size of service, diagnoses, disciplines, mode of care, types of interventions, ‘out-of-hours’ components (referrals, times, disciplines, mode of care, type of care), external education, use of measures, bereavement follow-up and complex grief provision. (3) Structured interviews with 21 UK service leads (six hospice inpatients, four hospital advisory and nine community teams) refined the criteria from (1) and (2), and provided four further contextual criteria (team purpose, funding, self-referral acceptance and discharge). Conclusion: In this innovative study, we derive 20 criteria to characterise and differentiate models of specialist palliative care – a major paradigm shift to enable accurate reporting and comparison in practice and research

Dust Devil Tracks

Dust devils that leave dark- or light-toned tracks are common on Mars and they can also be found on the Earth’s surface. Dust devil tracks (hereinafter DDTs) are ephemeral surface features with mostly sub-annual lifetimes. Regarding their size, DDT widths can range between ∼1 m and ∼1 km, depending on the diameter of dust devil that created the track, and DDT lengths range from a few tens of meters to several kilometers, limited by the duration and horizontal ground speed of dust devils. DDTs can be classified into three main types based on their morphology and albedo in contrast to their surroundings; all are found on both planets: (a) dark continuous DDTs, (b) dark cycloidal DDTs, and (c) bright DDTs. Dark continuous DDTs are the most common type on Mars. They are characterized by their relatively homogenous and continuous low albedo surface tracks. Based on terrestrial and martian in situ studies, these DDTs most likely form when surficial dust layers are removed to expose larger-grained substrate material (coarse sands of ≥500 μm in diameter). The exposure of larger-grained materials changes the photometric properties of the surface; hence leading to lower albedo tracks because grain size is photometrically inversely proportional to the surface reflectance. However, although not observed so far, compositional differences (i.e., color differences) might also lead to albedo contrasts when dust is removed to expose substrate materials with mineralogical differences. For dark continuous DDTs, albedo drop measurements are around 2.5 % in the wavelength range of 550–850 nm on Mars and around 0.5 % in the wavelength range from 300–1100 nm on Earth. The removal of an equivalent layer thickness around 1 μm is sufficient for the formation of visible dark continuous DDTs on Mars and Earth. The next type of DDTs, dark cycloidal DDTs, are characterized by their low albedo pattern of overlapping scallops. Terrestrial in situ studies imply that they are formed when sand-sized material that is eroded from the outer vortex area of a dust devil is redeposited in annular patterns in the central vortex region. This type of DDT can also be found in on Mars in orbital image data, and although in situ studies are lacking, terrestrial analog studies, laboratory work, and numerical modeling suggest they have the same formation mechanism as those on Earth. Finally, bright DDTs are characterized by their continuous track pattern and high albedo compared to their undisturbed surroundings. They are found on both planets, but to date they have only been analyzed in situ on Earth. Here, the destruction of aggregates of dust, silt and sand by dust devils leads to smooth surfaces in contrast to the undisturbed rough surfaces surrounding the track. The resulting change in photometric properties occurs because the smoother surfaces have a higher reflectance compared to the surrounding rough surface, leading to bright DDTs. On Mars, the destruction of surficial dust-aggregates may also lead to bright DDTs. However, higher reflective surfaces may be produced by other formation mechanisms, such as dust compaction by passing dust devils, as this may also cause changes in photometric properties. On Mars, DDTs in general are found at all elevations and on a global scale, except on the permanent polar caps. DDT maximum areal densities occur during spring and summer in both hemispheres produced by an increase in dust devil activity caused by maximum insolation. Regionally, dust devil densities vary spatially likely controlled by changes in dust cover thicknesses and substrate materials. This variability makes it difficult to infer dust devil activity from DDT frequencies. Furthermore, only a fraction of dust devils leave tracks. However, DDTs can be used as proxies for dust devil lifetimes and wind directions and speeds, and they can also be used to predict lander or rover solar panel clearing events. Overall, the high DDT frequency in many areas on Mars leads to drastic albedo changes that affect large-scale weather patterns

The present gravitational wave detection effort

Gravitational radiation offers a new non-electromagnetic window through which to observe the universe. The LIGO and Virgo Collaborations have completed a first joint data run with unprecedented sensitivities to gravitational waves. Results from searches in the data for a variety of astrophysical sources are presented. A second joint data run with improved detector sensitivities is underway, and soon major upgrades will be carried out to build Advanced LIGO and Advanced Virgo with expected improvements in event rates of more than 1000. In parallel there is a vigorous effort in the radio pulsar community to detect nHz gravitational waves via the timing residuals in an array of pulsars at different locations in the sky.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85430/1/jpconf10_203_012002.pd

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Recommended adult immunization schedule, United States, 2020

In October 2019, the Advisory Committee on Immunization Practices (ACIP) voted to approve the Recommended Adult Immunization Schedule for Ages 19 Years or Older, United States, 2020. The 2020 adult immunization schedule, available at www.cdc.gov/vaccines /schedules/hcp/imz/adult.html, summarizes ACIP recommendations in 2 tables and accompanying notes (Figure). The full ACIP recommendations for each vaccine are available at www.cdc.gov/vaccines/hcp/acip-recs/index.html. The 2020 schedule has also been approved by the director of the Centers for Disease Control and Prevention (CDC) and by the American College of Physicians (www .acponline.org), American Academy of Family Physicians (www.aafp.org), American College of Obstetricians and Gynecologists (www.acog.org), and American College of Nurse-Midwives (www.midwife.org)

Dexamethasone intravitreal implant in previously treated patients with diabetic macular edema : Subgroup analysis of the MEAD study

Background: Dexamethasone intravitreal implant 0.7 mg (DEX 0.7) was approved for treatment of diabetic macular edema (DME) after demonstration of its efficacy and safety in the MEAD registration trials. We performed subgroup analysis of MEAD study results to evaluate the efficacy and safety of DEX 0.7 treatment in patients with previously treated DME. Methods: Three-year, randomized, sham-controlled phase 3 study in patients with DME, best-corrected visual acuity (BCVA) of 34.68 Early Treatment Diabetic Retinopathy Study letters (20/200.20/50 Snellen equivalent), and central retinal thickness (CRT) 65300 \u3bcm measured by time-domain optical coherence tomography. Patients were randomized to 1 of 2 doses of DEX (0.7 mg or 0.35 mg), or to sham procedure, with retreatment no more than every 6 months. The primary endpoint was 6515-letter gain in BCVA at study end. Average change in BCVA and CRT from baseline during the study (area-under-the-curve approach) and adverse events were also evaluated. The present subgroup analysis evaluated outcomes in patients randomized to DEX 0.7 (marketed dose) or sham based on prior treatment for DME at study entry. Results: Baseline characteristics of previously treated DEX 0.7 (n = 247) and sham (n=261) patients were similar. In the previously treated subgroup, mean number of treatments over 3 years was 4.1 for DEX 0.7 and 3.2 for sham, 21.5 % of DEX 0.7 patients versus 11.1 % of sham had 6515-letter BCVA gain from baseline at study end (P = 0.002), mean average BCVA change from baseline was +3.2 letters with DEX 0.7 versus +1.5 letters with sham (P = 0.024), and mean average CRT change from baseline was -126.1 \u3bcm with DEX 0.7 versus -39.0 \u3bcm with sham(P < 0.001). Cataract-related adverse events were reported in 70.3 % of baseline phakic patients in the previously treated DEX 0.7 subgroup; vision gains were restored following cataract surgery. Conclusions: DEX 0.7 significantly improved visual and anatomic outcomes in patients with DME previously treated with laser, intravitreal anti-vascular endothelial growth factor, intravitreal triamcinolone acetonide, or a combination of these therapies. The safety profile of DEX 0.7 in previously treated patients was similar to its safety profile in the total study population

Methods for high-dimensonal analysis of cells dissociated from cyropreserved synovial tissue

Background: Detailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership RA/SLE Network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dimensional assays. Robust standardized protocols need to be developed before cellular phenotypes at a single cell level can be effectively compared across patient samples. Methods: Multiple clinical sites collected cryopreserved synovial tissue fragments from arthroplasty and synovial biopsy in a 10% DMSO solution. Mechanical and enzymatic dissociation parameters were optimized for viable cell extraction and surface protein preservation for cell sorting and mass cytometry, as well as for reproducibility in RNA sequencing (RNA-seq). Cryopreserved synovial samples were collectively analyzed at a central processing site by a custom-designed and validated 35-marker mass cytometry panel. In parallel, each sample was flow sorted into fibroblast, T-cell, B-cell, and macrophage suspensions for bulk population RNA-seq and plate-based single-cell CEL-Seq2 RNA-seq. Results: Upon dissociation, cryopreserved synovial tissue fragments yielded a high frequency of viable cells, comparable to samples undergoing immediate processing. Optimization of synovial tissue dissociation across six clinical collection sites with ~ 30 arthroplasty and ~ 20 biopsy samples yielded a consensus digestion protocol using 100 μg/ml of Liberase™ TL enzyme preparation. This protocol yielded immune and stromal cell lineages with preserved surface markers and minimized variability across replicate RNA-seq transcriptomes. Mass cytometry analysis of cells from cryopreserved synovium distinguished diverse fibroblast phenotypes, distinct populations of memory B cells and antibody-secreting cells, and multiple CD4+ and CD8+ T-cell activation states. Bulk RNA-seq of sorted cell populations demonstrated robust separation of synovial lymphocytes, fibroblasts, and macrophages. Single-cell RNA-seq produced transcriptomes of over 1000 genes/cell, including transcripts encoding characteristic lineage markers identified. Conclusions: We have established a robust protocol to acquire viable cells from cryopreserved synovial tissue with intact transcriptomes and cell surface phenotypes. A centralized pipeline to generate multiple high-dimensional analyses of synovial tissue samples collected across a collaborative network was developed. Integrated analysis of such datasets from large patient cohorts may help define molecular heterogeneity within RA pathology and identify new therapeutic targets and biomarkers

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials