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Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

BackgroundUC San Diego Health System (UCSDHS) is an academic medical center and integrated care network in the US-Mexico border area of California contiguous to the Mexican Northern Baja region. The COVID-19 pandemic deeply influenced UCSDHS activities as new public health challenges increasingly related to high population density, cross-border traffic, economic disparities, and interconnectedness between cross-border communities, which accelerated development of clinical collaborations between UCSDHS and several border community hospitals - one in the US, two in Mexico - as high volumes of severely ill patients overwhelmed hospitals.ObjectiveWe describe the development, implementation, feasibility, and acceptance of a novel critical care support program in three community hospitals along the US-Mexico border.MethodsWe created and instituted a hybrid critical care program involving: 1) in-person activities to perform needs assessments of equipment and supplies and hands-on training and education, and 2) creation of a telemedicine-based (Tele-ICU) service for direct patient management and/or consultative, education-based experiences. We collected performance metrics surrounding adherence to evidence-based practices and staff perceptions of critical care delivery.FindingsIn-person intervention phase identified and filled gaps in equipment and supplies, and Tele-ICU program promoted adherence to evidence-based practices and improved staff confidence in caring for critically ill COVID-19 patients at each hospital.ConclusionA collaborative, hybrid critical care program across academic and community centers is feasible and effective to address cross-cultural public health emergencies.

ObjectivesTo examine reactions to the proposed improvements to standard Kaplan-Meier plots, the standard way to present time-to-event data, and to understand which (if any) facilitated better depiction of (1) the state of patients over time, and (2) uncertainty over time in the estimates of survival.DesignA survey of stakeholders' opinions on the proposals.SettingA web-based survey, open to international participation, for those with an interest in visualisation of time-to-event data.Participants1174 people participated in the survey over a 6-week period. Participation was global (although primarily Europe and North America) and represented a wide range of researchers (primarily statisticians and clinicians).Main outcome measuresTwo outcome measures were of principal importance: (1) participants' opinions of each proposal compared with a 'standard' Kaplan-Meier plot; and (2) participants' overall ranking of the proposals (including the standard).ResultsMost proposals were more popular than the standard Kaplan-Meier plot. The most popular proposals in the two categories, respectively, were an extended table beneath the plot depicting the numbers at risk, censored and having experienced an event at periodic timepoints, and CIs around each Kaplan-Meier curve.ConclusionsThis study produced a high response number, reflecting the importance of graphics for time-to-event data. Those producing and publishing Kaplan-Meier plots-both authors and journals-should, as a starting point, consider using the combination of the two favoured proposals.

ObjectiveTo assess the adequacy of reporting of non-inferiority trials alongside the consistency and utility of current recommended analyses and guidelines.DesignReview of randomised clinical trials that used a non-inferiority design published between January 2010 and May 2015 in medical journals that had an impact factor >10 (JAMA Internal Medicine, Archives Internal Medicine, PLOS Medicine, Annals of Internal Medicine, BMJ, JAMA, Lancet and New England Journal of Medicine).Data sourcesOvid (MEDLINE).MethodsWe searched for non-inferiority trials and assessed the following: choice of non-inferiority margin and justification of margin; power and significance level for sample size; patient population used and how this was defined; any missing data methods used and assumptions declared and any sensitivity analyses used.ResultsA total of 168 trial publications were included. Most trials concluded non-inferiority (132; 79%). The non-inferiority margin was reported for 98% (164), but less than half reported any justification for the margin (77; 46%). While most chose two different analyses (91; 54%) the most common being intention-to-treat (ITT) or modified ITT and per-protocol, a large number of articles only chose to conduct and report one analysis (65; 39%), most commonly the ITT analysis. There was lack of clarity or inconsistency between the type I error rate and corresponding CIs for 73 (43%) articles. Missing data were rarely considered with (99; 59%) not declaring whether imputation techniques were used.ConclusionsReporting and conduct of non-inferiority trials is inconsistent and does not follow the recommendations in available statistical guidelines, which are not wholly consistent themselves. Authors should clearly describe the methods used and provide clear descriptions of and justifications for their design and primary analysis. Failure to do this risks misleading conclusions being drawn, with consequent effects on clinical practice.

To date, the OCAM2 system has demonstrated to be the fastest and lowest noise production ready wavefront sensor, achieving 2067 full frames per second with subelectron readout noise. This makes OCAM2 the ideal system for natural as well as continuous wave laser guide star wavefront sensing. In this paper we present the new gated version of OCAM2 named OCAM2-S, using E2V’s CCD219 sensor with integral shutter. This new camera offers the same superb characteristics than OCAM2 both in terms of speed and readout noise but also offers a shutter function that makes the sensor only sensitive to light for very short periods, at will. We will report on gating time and extinction ratio performances of this new camera. This device opens new possibilities for Rayleigh pulsed lasers adaptive optics systems. With a shutter time constant well below 1 microsecond, this camera opens new solutions for pulsed sodium lasers with backscatter suppression or even spot elongation minimization for ELT LGS. This camera has been successfully used for the first time on the CANARY instrument on the William Herschel Telescope. The final phase of CANARY is a demonstrator of a single MOAO channel for the proposed EAGLE instrument on the future European ELT. We will report on-sky performance with this instrument.

MOSAIC is the proposed multiple object spectrograph for the E-ELT that will eventually combine two AO observing modes within a single instrument. MOSAIC will contain up to 20 open-loop multiple object AO channels feeding NIR IFUs in addition to up to 200 seeing-limited (or GLAO corrected) VIS – NIR fibre pickoffs. Wavefront tomography will be implemented using a combination of LGS and a few high-order NGS distributed across the field with the wavefront correction applied in a split open/closed loop configuration. MOSAIC will be the only E-ELT instrument planned that can utilize the full 10 arcminute diameter field of view, enabling highly efficient observing modes for this workhorse instrument. Use of the full E-ELT field inevitably requires a closer integration between the telescope control system and the instrument AO systems, however this can bring several potential benefits to overall system performance. Here we present the initial design concept and baseline performance of the MOSAIC instrument and AO system(s) taking advantage of the CANARY on-sky results and inheriting from the previous Phase A study of EAGLE. Finally, we will highlight areas of system performance and calibration that will require further analysis and trade-off during the course of the upcoming Phase A study.

We present a concept for visible near-diffraction limited lucky imaging with full-sky laser assisted adaptive optics.Simulation results are given, along with first on-sky measurements taken with the CANARY AO system on theWilliam Herschel Telescope, and extension to ELT scales.We also present a study of readout noise in EMCCD and sCMOS detectors, with findings that are perhapssurprising when compared with naive models of sCMOS noise. We discuss the relative trade-offs of these detectorsfor ELT-scale AO and lucky imaging.Finally we introduce the concept of real-time simulation, necessary for integration and verification of ELT-scale AO systems, and provide details of the system developed for CANARY.

Current Laser Guide Star (LGS) Adaptive Optics (AO) systems disregard all tip-tilt wavefront information received from the LGS Wavefront Sensors (WFS), as it is considered irretrievably entangled with the up-link turbulence that the laser encounters as it passes through the atmosphere to form a guide star. Consequently, they must still observe a Natural Guide Star (NGS) in order to correct for tip-tilt aberrations.A method has recently been presented that use the tomographic capabilities of centre-launched, multi-LGS AO systems to predict the LGS uplink turbulence and hence allow correction with a reduced requirement on the NGS, or potentially no NGS requirement at all for some scientific applications. This method is summarised here, and its limitations discussed. Due to the increased separation of the laser beams at higher altitude, the method is more effective for correction of tip-tilt from high altitude turbulence, with performance approaching that of tomographic LGS AO with a tip-tilt NGS. The method is less successful for correcting tip-tilt contributions from low altitudes, though potential mitigation of this is considered.We finally discuss the methods potential for ELT scale operation. Due to the large aperture size, and large LGS separation, it is expected that the method would be more effective for larger telescopes.