The Pediatric Cell Atlas: defining the growth phase of human development at single-cell resolution

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan

Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study

Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2–7 months after hospital discharge and a later time point 10–14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4–6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5–8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (–19%; 95% CI –20 to –16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18–39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27–41% of this effect. Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Comparative isotopic and chemical geochronometry of monazite, with implications for U-Th-Pb dating by electron microprobe: An example from metamorphic rocks of the eastern Wyoming Craton (U.S.A.)

Polygenetic monazite grains in diverse Precambrian crystalline rocks from the Black Hills, South Dakota, have been analyzed in situ by ion and electron microprobe methods (SHRIMP and EMP), to evaluate the accuracy and precision of EMP ages determined using a new analytical protocol that incorporates improved background acquisition and interference corrections. Parallel evaluations were conducted by comparing EMP chemical and SHRIMP isotopic ages at regional-, rock-, and grain-scales. The monazite data set includes 354 EMP chemical analyses from 26 grains in six metamorphic rocks, which resolve into 54 age-composition domains, and 31 SHRIMP isotopic ages from 13 grains in one of the rocks, with six grains microanalyzed in common by the two methods. The data set also includes monazite-bearing garnets in two of the rocks, whose isotopic compositions were analyzed using Pb stepwise-leaching (PbSL) methods. Both the EMP and SHRIMP data sets reveal a continuum of apparent monazite ages spanning a ∼1790-1680 Ma timeframe, with a relatively high probability of ages at ∼1755 and ∼1715 Ma that correspond spatially to core and rim domains. PbSL ages of ∼1742 and ∼1734 Ma obtained from monazite-bearing garnet in two rocks are intermediate compared to the corresponding EMP ages, and are thereby interpreted as mixed ages. EMP data for two grains in the structurally deepest of the six rocks record ∼1785 and ∼1755 Ma ages in the cores and (higher-Y and lower-Th) rims, respectively, and these results are duplicated by SHRIMP ages in these and/or other grains from the same rock. Overall, the EMP, SHRIMP, and PbSL ages are internally consistent at the various scales of observation, which serves to validate EMP chemical dating as an accurate and precise method of discerning monazite age populations in polymetamorphic terrains. The EMP data set is interpreted geologically as reflecting multiple episodes of monazite growth that are provisionally related to known metamorphic events in the Black Hills. Taking the most precise EMP data at face value, it is possible to resolve the timing of the two older events at ≤1784 ± 4 Ma (or ≤1786 ± 6 Ma) and 1756 ± 3 Ma (or 1753 ± 4 Ma), with 95% confidence. These events are considered to be related to sequential episodes of N-directed thrusting and ∼E-W compression associated with Paleoproterozoic crustal assembly in the mid-continent. A younger metamorphism, related to granite intrusion known to have occurred at 1715 ± 3 Ma, is dated independently at 1717 ± 2 Ma from the EMP monazite ages.</p

Geophysical insights into the Transition fault debate: Propagating strike slip in response to stalling Yakutat block subduction in the Gulf of Alaska

On the basis of faulting mapped on seismic reflection and bathymetric data, seismicity, current plate motions, and evidence that the Yakutat block may be anomalously thick, we propose a tectonic model for Yakutat-Pacific interactions, including the often-debated Transition fault. To the east, deformation associated with the Queen Charlotte–Fairweather fault system is extending offshore, facilitating westward propagation of strike-slip motion along the eastern segment of the Transition fault. To the west, the oblique-slip Pamplona zone and Transition faults merge at an embayment in the continental margin, where a north-south dextral strike-slip fault within the Pacific plate, illuminated by the 1987–1992 earthquake swarm, intersects the Pacific-Yakutat tectonic boundary. These fault patterns are consistent with modern plate motions and reflect a plate boundary reorganization that may be caused by resistance to subduction by the Yakutat block, a possible moderate-sized oceanic plateau

Lead-isotope and trace-element geochemistry of Paleoproterozoic metasedimentary rocks in the Lead and Rochford basins (Black Hills, South Dakota, USA):implications for genetic models, mineralization ages, and sources of ore leads for the Homestake gold deposit

Mixed, silicate–carbonate–sulfide facies, banded iron formations with elevated detrital components were deposited in the Northern Black Hills during middle Paleoproterozoic time, between 2.012 and 1.974 Ga (Homestake Iron Formation and equivalents) and at ≤1.887 Ga (Rochford Iron Formation). These iron formations, deposited atop shales and basalts in intracontinental rifted basins separated in time by ∼80–130 Myr, are the hosts of extensive, late Paleoproterozoic gold mineralization. Gold/sulfide ore bodies occur within dilated segments of late-stage ductile–brittle shears that formed after isoclinal folding related to Wyoming–Superior continental collision. Lead stepwise leaching (PbSL) data for monazite-bearing garnet separated from a sample of Homestake Iron Formation has yielded an isochron age of 1746 ± 10Ma (2σ; MSWD = 0.42), which represents a maximum age for both the isoclinal folding and subsequent gold mineralization. Monazite-bearing garnet from a nearby “Harney Peak”-type granitic pegmatite, believed to be coeval with latest-stage, semibrittle shears and quartz veins that crosscut Homestake ore bodies, has yielded a PbSL isochron age of 1713 ± 10 Ma (2σ, MSWD = 4.1), which probably represents a minimum age for the gold event. Pb isotopes of sulfides from “replacement ore” and “shear ore” within the Homestake Iron Formation cannot distinguish between these distinct ore types. However, both Pb isotopes and REY (rare earth and yttrium) abundances indicate slight disequilibrium between the ore sulfides and the barren iron formation, thus revealing an epigenetic (sensu stricto) component to the gold mineralization. The Pb-isotope characteristics of the ore further reflect an admixed component with low 232Th/204Pb and variable Th/U ratios in addition to compositions directly derived from BIF-typical leads. This added component corresponds to Pb from the anoxic metasedimentary rocks directly underlying the iron formations and from the nearby pegmatitic granite. The apparent Pb-isotopic match between ore and granite is further consistent with the PbSL data for “shear ore”-type arsenopyrite, which define an isochron age of 1719 +38-45 Ma (2σ, MSWD = 0.2), and by a striking overlap of the Pb-isotopic data fields defined by the Homestake galenas and pegmatitic feldspars. The Precambrian ore leads are therefore best explained as mixtures of magmatic-hydrothermal and host-rock-mobilized leads. The Lead area also contains significant gold-bearing deposits of Tertiary age, which are hosted in both Paleoproterozoic and Phanerozoic rocks. Tertiary mineralization was temporally and spatially related to coeval plutons emplaced during Laramide uplift of the Black Hills and represents the final mineralization event recognized in the Homestake Mine area. Like the Precambrian galena leads, the leads of Tertiary galena hosted by middle Paleoproterozoic rocks (including the Homestake Iron Formation) define a trend best explained by mixtures of Pb derived from magmatic fluids exsolved from Tertiary intrusives and Pb leached from the same country rocks that contaminated the granite-derived hydrothermal fluids ascending through them during the much earlier shearing-and-mineralization event inferred at ∼1730–1715Ma.</p

Seismic images of the Transition fault and the unstable Yakutat-Pacific-North American triple junction

In southern Alaska, the Pacific plate and Yakutat terrane subduct beneath the North American plate along the Aleutian Trench and Pamplona zone, respectively, and are sliding past each other at minimal rates along the Transition fault. As the deformation front of the Pamplona zone stepped eastward during the Pliocene–Pleistocene, the Pacific–North American–Yakutat triple junction became unstable. Four recent seismic images reveal that the Transition fault changes from a single strike-slip boundary east of the deformation front to three strands that step increasingly seaward between the deformation front and the Aleutian Trench. The southern two strands deform the Pacific crust, and the outermost of these became increasingly convergent sometime since 1 Ma, as demonstrated by young growth strata. We propose that this internal deformation of the Pacific plate is an attempt to reattain stability, which can only be reached by creating a tectonic boundary collinear with the Pamplona zone. The plate reorganization will result in initiation of subduction such that a portion of former Pacific crust will become accreted to the North American plate. Such accretion events caused by triple-junction instability may be an important mechanism for transferring oceanic crust to continental margins