Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

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

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

Exploring user requirements for a lower body soft exoskeleton to assist mobility

Understanding the requirements of potential users is crucial to the successful design of wearable exoskeleton systems. Considering user requirements throughout the design process optimises the likelihood of user uptake and facilitates adherence to the use of wearable systems. This chapter describes the application of a user-centred design approach to the development of a soft lower body assistive exoskeleton for individuals with mild to moderate mobility impairment. Examples of the identification and characterisation of user groups, the use of qualitative and quantitative research methods to explore user requirements, and the implications of user requirements for soft exoskeleton technologies are presented

Online work force analyzes social media to identify consequences of an unplanned school closure – using technology to prepare for the next pandemic

We used the social media-monitoring platform Radian6 (San Francisco, CA) to retrospectively capture social media posts related to the Chicago City School District closure in September 2012. Social media in dataset include posts from Twitter, Facebook, blogs, forums, and comments between September 8 and September 12, (two days before the strike started to two days after the strike ended). We used the following combination of search terms: “strike Chicago” AND “breakfast” OR “childcare” OR “daycare” OR “lunch” OR “parent”.  A proximity score of “5” was applied to the terms “strike” and “Chicago” (on a scale of 1–20, with 1 being exact [i.e., strike and Chicago together]).<div><br></div><div>Column headings include:  Unique post identifying number (NUMBER), post content (CONTENT), social media provider (MEDIA_PROVIDER), and publishing date/time (PUBLISH_DATE).  </div><div><br></div><div>These posts were reviewed and categorized as relevant (related to impact of closure on students and their families) or irrelevant (describing political aspects of strike, welfare system, or other unrelated topics).  Relevant posts were further analyzed for underlying sentiment (positive, neutral, or negative).</div

Exhumation of the Coastal Metamorphic Belt Above the Subduction‐to‐Transform Transition, in the Southeast Caribbean Plate Corner

Plate corners that transition from subduction to transform motion can result in complex deformation. The southeastern corner of the Caribbean plate is a site where active westward subduction of the oceanic South American plate transitions to transform motion along continental South America. The Northern Range (Trinidad) and Paria (Venezuela) metamorphic mountains are located directly above this eastward propagating plate transition zone. We examined the exhumation history of the Northern Range and eastern Paria using apatite fission track (AFT) and apatite and zircon (U-Th)/He (AHe and ZHe, respectively) thermochronology on 21 bedrock samples. These samples yield ages of ∼43–6 Ma (ZHe: aliquots), ∼20–4 Ma (AFT: pooled) and ∼5–2 Ma (AHe: aliquots). Along strike of the mountains, our new and published samples show a gradual eastward increase in age. Thermal modeling reveals two phases of rapid cooling and inferred exhumation that post-dates oblique collision and that migrated from west to east. We record an ∼six-fold increase in cooling and exhumation between ∼13–9 Ma in the Paria Peninsula and western Northern Range; a deceleration followed this rapid exhumation at ∼7 and 5 Ma. Synchronous with the deceleration in the west, exhumation of the eastern Northern Range increased ∼4 Ma. These post-collisional changes in exhumation constrain the inversion to east-side-up tilting of the Northern Range to ∼4 Ma. We interpret the timing and pattern of exhumation since the mid-Miocene to be consistent with the time-transgressive processes produced by an eastward propagating lithospheric subduction-transform edge propagator fault

Exhumation of the Coastal Metamorphic Belt Above the Subduction‐to‐Transform Transition, in the Southeast Caribbean Plate Corner

Plate corners that transition from subduction to transform motion can result in complex deformation. The southeastern corner of the Caribbean plate is a site where active westward subduction of the oceanic South American plate transitions to transform motion along continental South America. The Northern Range (Trinidad) and Paria (Venezuela) metamorphic mountains are located directly above this eastward propagating plate transition zone. We examined the exhumation history of the Northern Range and eastern Paria using apatite fission track (AFT) and apatite and zircon (U-Th)/He (AHe and ZHe, respectively) thermochronology on 21 bedrock samples. These samples yield ages of ∼43–6 Ma (ZHe: aliquots), ∼20–4 Ma (AFT: pooled) and ∼5–2 Ma (AHe: aliquots). Along strike of the mountains, our new and published samples show a gradual eastward increase in age. Thermal modeling reveals two phases of rapid cooling and inferred exhumation that post-dates oblique collision and that migrated from west to east. We record an ∼six-fold increase in cooling and exhumation between ∼13–9 Ma in the Paria Peninsula and western Northern Range; a deceleration followed this rapid exhumation at ∼7 and 5 Ma. Synchronous with the deceleration in the west, exhumation of the eastern Northern Range increased ∼4 Ma. These post-collisional changes in exhumation constrain the inversion to east-side-up tilting of the Northern Range to ∼4 Ma. We interpret the timing and pattern of exhumation since the mid-Miocene to be consistent with the time-transgressive processes produced by an eastward propagating lithospheric subduction-transform edge propagator fault

XoSoft - A Vision for a Soft Modular Lower Limb Exoskeleton

XoSoft is an EU project that proposes the development of a modular soft lower-limb exoskeleton to assist people with mobility impairments. It aims to be user friendly and comfortable to wear, with a significant impact on the person’s mobility and health, on their independence and quality of life. Being a modular system, it comprises of ankle, knee and hip elements, which can be used individually or combined and used unilaterally or bilaterally. XoSoft follows a user centered design strategy achieved by involving primary, secondary and tertiary end users as participatory stakeholders in the design and development process. Preliminary findings of the interviews with the different users groups are presented in this paper. Advanced textiles and smart materials are being developed to create sensing, variable stiffness joints and flexible tactile sensors. Control will be through biomimetics to identify the user’s motion and intention and to determine and provide the appropriate level of assistance. Connected health connectivity and analysis will enable the wearer and their clinicians/therapist to review activity information. The concept will be tested extensively in the lab, and subject to trials in clinical settings and home environments