Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tundra environments in the Neogene Sirius Group, Antarctica: evidence from the geological record and coupled atmosphere–vegetation models

The Neogene Meyer Desert Formation, Sirius Group, at Oliver Bluffs in the Transantarctic Mountains, contains a sequence of glacial deposits formed under a wet-based glacial regime. Within this sequence fluvial deposits have yielded fossil plants that, along with evidence from fossil insects, invertebrates and palaeosols, indicate the existence of tundra conditions at 85°S during the Neogene. Mean annual temperatures of c. –12 °C are estimated, with short summer seasons with temperatures up to +5 °C. The current published date for this formation is Pliocene, although this is hotly debated. Reconstructions produced by the TRIFFID and BIOME 4 vegetation models, utilizing a Pliocene climatology derived from the HadAM3 General Circulation Model (running with prescribed boundary conditions from the US Geological Survey PRISM2 dataset), also predict tundra-type vegetation in Antarctica. The consistency of the model outputs with geological evidence demonstrates that a Pliocene age for the Meyer Desert Formation is consistent with proxy environmental reconstructions and numerical model reconstructions for the mid-Pliocene. If so, the East Antarctic Ice Sheet has behaved in a dynamic manner in the recent geological past

Three dimensional sedimentary architecture of a large, mid-channel sand braid bar, Jamuna River, Bangladesh

The three-dimensional subsurface alluvial architecture of a large (approximately 3 km long, 1 km wide, 12 m high), mid-channel sand braid bar in the Jamuna River, Bangladesh is described. Evolution of the bar and its depositional characteristics are assessed from a unique combination of ground-penetrating radar surveys, vibracoring, and trenching that are allied to a series of bathymetric surveys taken during growth of the bar over a 29-month period. This methodology permits identification of the formative processes of different packages of braid-bar sedimentation and provides a facies model for deposition within the entire bar. Mid-channel bar growth occurred in a region of flow expansion and was probably initiated by the stalling and amalgamation of large dunes. These dunes created a bar-core that grew by (i) propagation of a downstream-accreting slipface, (ii) vertical accretion through stacking of dunes on both bar stoss and top, and (iii) lateral accretion on the bar margins during recession of the flood hydrograph. Braid-bar sedimentation is dominated by four radar facies: (1) large-scale, predominantly planar, dipping reflections interpreted as cross-stratification, up to 8 m in height and greater than 100 m in width, that is produced by the cross-channel migration of bar margins, (2) medium-scale, trough-shaped and planar discontinuous reflections interpreted as cross-stratification up to 4 m in height and 300 m wide, that is deposited from large, sinuous-crested sand dunes, (3) discontinuous reflections, up to 2 m high and 30 m wide, interpreted as small-scale trough cross-stratification, that is the product of smaller sinuous-crested dunes, and (4) high-amplitude, undulating reflections interpreted as mud drapes, deposited in regions of slow flow, often in the bar-tail region at low stage. Dune size decreases vertically within the bar, in response to the progressively shallower flows on the emerging bar top. Later evolution of the bar, as one anabranch channel became dominant, created a 1.5 km extension to the bar tail with an 8 m high, angle-of-repose, bar-margin slipface, formed by flow transverse to the long axis of the bar. Seven styles of deposition can be defined that constitute the alluvial architecture: bar-margin slipface, vertical accretion in channel, bar-top vertical accretion, upstream accretion, lateral accretion, downstream accretion, and low-stage mud drapes. A model of braid-bar sedimentation is presented that shares many similarities with previous studies of smaller sand-bed braid bars with the dominance of dune-scale cross-stratification, the presence of large-scale, bar-margin cross-stratification, and the occurrence of lateral, vertical, upstream, and downstream accretion. However, the contribution of the bar-margin facies to the preserved stratigraphy highlighted herein may have been underestimated in previous models of braided rivers in which the braid bars were migrating slowly. This study suggests a scale invariance in several aspects of mid-channel bar sedimentation in sand-bed rivers and proposes a model of braid-bar sedimentation that may be applied widely within studies of braided alluvial architecture

The Behavioural Status Index (BSI) Descriptive studies within a forensic context

SIGLEAvailable from British Library Document Supply Centre-DSC:DXN030672 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The Influence of Three‐Dimensional Topography on Turbulent Flow Structures Over Dunes in Unidirectional Flows

Dunes are the most prevalent bedform present in sand-bedded rivers and their morphology typically comprises multiple scales of three-dimensional topography. However, our understanding of flow over dunes is predicated largely on two-dimensional models, a condition which is rare in nature. Here, we present results of Large Eddy Simulations over a static, three-dimensional dune field, using a two- and three- dimensional topographic realisation, to investigate the interaction between bed topography and turbulent flow structures. We show that flow over two-dimensional bedforms increases the velocity over the stoss slope and reduces the size of the leeside separation zone as compared to 3D topography. Flow over three-dimensional bedforms generates twice as many vortices as over two-dimensional bedforms, and these vortices are longer, wider and taller than flow over their two-dimensional counterparts. Turbulence is dominated by hairpin-shaped vortices and Kelvin-Helmholtz instabilities that interact with the bed in the brink point region of the dune crest and down the lee slope, and generate high shear stresses for long durations. These results are used to propose a new conceptual model showing the differences between flow over two- and three-dimensional bedforms. The findings highlight how the size, morphology and stacking of coherent flow structures into larger flow superstructures may be critical in sediment entrainment, and may dictate the relationship between event duration and magnitude that drives sediment impulses at the bed. This will ultimately lead to an increased in the three-dimensionality of bedform morphology