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An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular–immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood–brain barrier as a possible target to treat age-related neurodegeneration. The detrimental effects of aged blood on cognition and nervous system function in mice can be combatted by targeting brain endothelial cell dysfunction via inhibition of aberrant VCAM1 signaling at the blood–brain barrier.

An aged circulatory environment can promote brain dysfunction and we hypothesized that the blood-brain barrier (BBB) mediates at least some of these effects. We observe brain endothelial cells (BECs) in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of Vascular Cell Adhesion Molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, the shed, soluble form of VCAM1 is prominently increased in the aged circulation of humans and mice, and aged plasma is sufficient to increase VCAM1 expression in cultured BECs and young mouse hippocampi. Systemic anti-VCAM1 antibody or genetic ablation of VCAM1 in BECs counteracts the detrimental effects of aged plasma on young brains and reverses aging aspects in old mouse brains. Thus, VCAM1 is a negative regulator of adult neurogenesis and inducer of microglial reactivity, establishing VCAM1 and the luminal side of the BBB as possible targets to treat age-related neurodegeneration.

Light‐level geolocator tags use ambient light recordings to estimate the whereabouts of an individual over the time it carried the device. Over the past decade, these tags have emerged as an important tool and have been used extensively for tracking animal migrations, most commonly small birds. Analysing geolocator data can be daunting to new and experienced scientists alike. Over the past decades, several methods with fundamental differences in the analytical approach have been developed to cope with the various caveats and the often complicated data. Here, we explain the concepts behind the analyses of geolocator data and provide a practical guide for the common steps encompassing most analyses – annotation of twilights, calibration, estimating and refining locations, and extraction of movement patterns – describing good practices and common pitfalls for each step. We discuss criteria for deciding whether or not geolocators can answer proposed research questions, provide guidance in choosing an appropriate analysis method and introduce key features of the newest open‐source analysis tools. We provide advice for how to interpret and report results, highlighting parameters that should be reported in publications and included in data archiving. Finally, we introduce a comprehensive supplementary online manual that applies the concepts to several datasets, demonstrates the use of open‐source analysis tools with step‐by‐step instructions and code and details our recommendations for interpreting, reporting and archiving. Over the past decade, light‐level geolocator tags have emerged as an important tool for tracking animals. However, due to various caveats, the translation of light recordings into location estimates can be daunting. In this 'How to…' paper, we provide a practical guide for the analysis of geolocator data by describing good practices and discussing common pitfalls.

The cloud imaging and particle size (CIPS) experiment is one of three instruments on board the Aeronomy of Ice in the Mesosphere (AIM) spacecraft that was launched into a 600 km Sun‐synchronous orbit on 25 April 2007. CIPS images have shown distinct wave patterns and structures in polar mesospheric clouds (PMCs), around the summertime mesopause region, which are qualitatively similar to structures seen in noctilucent clouds (NLCs) from ground‐based photographs. The structures in PMC are generally considered to be manifestations of upward propagating atmospheric gravity waves (AGWs). Variability of AGW effects on PMC reported at several lidar sites has led to the notion of longitudinal differences in this relationship. This study compares the longitudinal variability in the CIPS‐observed wave occurrence frequency with CIPS‐measured PMC occurrence frequency and albedo along with mesospheric temperatures measured by the sounding of the atmosphere using broadband emission radiometry instrument on board the Thermosphere Ionosphere Mesosphere Energetics and Dynamics spacecraft. Our results for the latitude ranges between 70° and 80° show a distinct anticorrelation of wave structures with cloud occurrence frequency and correlations with temperature perturbations for at least two of the four seasons analyzed, supporting the idea of gravity wave‐induced cloud sublimation. The locations of the observed wave events show regions of high wave activity in both hemispheres. In the Northern Hemisphere, while the longitudinal variability in observed wave structures show changes from the 2007–2008 seasons, there exist regions of both low and high wave activities common to the two seasons. These persistent features may explain some of the observed differences in PMC activity reported by ground‐based lidar instruments distributed at different longitudes. The statistical distribution of horizontal scales increases with wavelength up to at least 250 km. We also discuss the possibility of atmospheric tides, especially the nonmigrating semidiurnal tide, aliasing our observations and affecting the results presented in this analysis.

ObjectivesTo evaluate the efficacy and safety of avacopan in the subgroup of patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis receiving background induction therapy with rituximab in the phase 3 ADVOCATE trial.MethodsKey efficacy outcomes were remission at week 26 and sustained remission at week 52. Additional outcomes included the Glucocorticoid Toxicity Index, estimated glomerular filtration rate, urinary albumin to creatinine ratio, health-related quality of life and safety.ResultsOf the 330 patients who received study medication, 214 (64.8%) received rituximab (once weekly for 4 weeks), with a mean age of 59.8 years; 163 (76.2%) had renal vasculitis and 125 (58.4%) were newly diagnosed. Remission at week 26 and sustained remission at week 52 were achieved by 83/107 (77.6%) and 76/107 (71.0%) patients in the avacopan group and 81/107 (75.7%) and 60/107 (56.1%) in the prednisone taper group, respectively. The relapse rate, recovery of renal function, speed of reduction in albuminuria and glucocorticoid toxicity favoured the avacopan group. Serious adverse events occurred in 34.6% and 39.3% of patients in the avacopan and prednisone taper groups, respectively.ConclusionsThese data suggest that in patients with ANCA-associated vasculitis receiving rituximab, efficacy of treatment with avacopan compared with a prednisone taper was similar at week 26 and greater at week 52, with a favourable safety profile. In addition, avacopan was associated with improved renal outcomes and lower glucocorticoid toxicity. These results demonstrate the efficacy and safety of avacopan in patients receiving background induction therapy with rituximab.Trial registration number NCT02994927.

BackgroundImmunocompromised individuals are at substantially increased risk of severe acute respiratory infection (SARI), often compounded by inadequate response to vaccination. We assessed the prevalence of immunocompromising conditions (ICs) among hospitalized SARI patients, overall and by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) status, focusing on temporal trends during the coronavirus disease 2019 (COVID-19) pandemic. We hypothesized that IC prevalence among SARS-CoV-2-positive SARI patients may have increased over time due to increasing background rates of SARS-CoV-2 exposure and differential vaccination coverage and efficacy among those with IC.MethodsWe conducted a secondary data analysis of 5280 adults (≥ 18 years) hospitalized with SARI, enrolled in the COVIDRIVE study from five hospitals in Belgium, Italy, and Spain (June 2021-May 2023) and tested for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR). IC prevalence (including 95% confidence intervals [CIs)] was assessed using two definitions (main and alternative), excluding and including cancer patients. Changes in IC prevalence over time were assessed using linear trend analysis.ResultsAmong the 5280 SARI cases, IC prevalence by main definition was 13.9% (95% CI: 12.9–14.8) overall, increasing from 8.3% (95% CI: 3.7–15.8) to a peak of 22.0% (95% CI: 17.9–26.4) in Q3 2022; by alternative definition, IC prevalence was 28.8% (95% CI: 27.6–30.0) overall, increasing from 18.8% (95% CI: 11.5–28.0) to a peak of 38.5% (95% CI: 32.7–44.5) in Q2 2023. Among the 1924 SARS-CoV-2-positive cases, IC prevalence by main definition was 14.2% (95% CI: 12.7–15.9) overall, increasing from 3.4% (95% CI: 0.1–17.8) to a peak of 23.8% (95% CI: 17.4–31.1) in Q3 2022; by alternative definition, IC prevalence was 29.6% (95% CI: 27.6–31.7) overall, increasing from 3.4% (95% CI: 0.1–17.8) to a peak of 46.8% (95% CI: 32.1–61.9) in Q2 2023. The larger observed increase in IC prevalence (by both definitions) over time among SARS-CoV-2-positives, relative to SARI patients without SARS-CoV-2, was statistically significant.ConclusionsImmunocompromised individuals represent a high proportion of hospitalized SARI cases, with results suggesting IC prevalence was higher during later periods of the COVID-19 pandemic. As immunocompromised individuals often respond inadequately to vaccination, alternative strategies are needed to better protect this vulnerable group.

Marketing authorization holders of vaccines typically need to report brand-specific vaccine effectiveness (VE) to the regulatory authorities as part of their regulatory obligations. COVIDRIVE (now id. DRIVE) is a European public–private partnership for respiratory pathogen surveillance and studies of brand-specific VE with long-term follow-up. We report the final VE results from a two-dose primary series AZD1222 (ChAdOx1 nCoV-19) vaccine schedule in ≥18-year-old individuals not receiving boosters. Patients (N = 1,333) hospitalized with severe acute respiratory infection at 14 hospitals in Austria, Belgium, Italy, and Spain were included in the test-negative case–control study in 2021–2023. Absolute VE was calculated using generalized additive model (GAM), generalized estimating equation (GEE), and spline-based area under the curve (AUC, measuring VE up to 6 months after the last dose of AZD1222). Overall VE (against coronavirus disease 2019 [COVID-19] hospitalization) of an AZD1222 primary series was estimated as 65% using GEE (95% confidence interval [CI]: 52.9–74.5), and 69% using GAM (95% CI: 50.1–80.9) over the 22-month study period (comparator group: unvaccinated patients). The AUC of the spline-based VE estimate was 74.1% (95% CI: 60.0–88.3). VE against hospitalization in study participants who received their second AZD1222 dose 2 months or less before hospitalization was 86% using GEE (95% CI: 77.8–91.4), 93% using GAM (95% CI: 67.2–98.6). During this study period, where mainly the severe acute respiratory syndrome coronavirus 2 Omicron variant was circulating, a two-dose primary series AZD1222 vaccination conferred protection against COVID-19 hospitalization up to at least 6 months after the last dose.

Coronavirus Disease 2019 (COVID-19) instigated a flurry of clinical research activity. The unprecedented pace with which trials were launched left an early void in data standardization, limiting the potential for subsequent data pooling. To facilitate data standardization across emerging studies, the National Heart, Lung, and Blood Institute (NHLBI) charged two groups with harmonizing data collection, and these groups collaborated to create a concise set of COVID-19 Common Data Elements (CDEs) for clinical research. Our iterative approach followed three guiding principles: 1) draw from existing multi-center COVID-19 clinical trials as precedents, 2) incorporate existing data elements and data standards whenever possible, and 3) alignment to data standards that facilitate data sharing and regulatory submission. We also supported rapid implementation of the CDEs in NHLBI-funded studies and iteratively refined the CDEs based on feedback from those study teams. The NHLBI COVID-19 CDEs are publicly available and being used for current COVID-19 clinical trials. CDEs are organized into domains, and each data element is classified within a three-tiered prioritization system. The CDE manual is hosted publicly at https://nhlbi-connects.org/common_data_elements with an accompanying data dictionary and implementation guidance. The NHLBI COVID-19 CDEs are designed to aid data harmonization across studies to achieve the benefits of pooled analyses. We found that organizing CDE development around our three guiding principles focused our efforts and allowed us to adapt as COVID-19 knowledge advanced. As these CDEs continue to evolve, they could be generalized for use in other acute respiratory illnesses.

BackgroundThis study evaluated the efficacy and safety of avacopan versus a prednisone taper in the subgroup of patients with antineutrophil cytoplasmic antibody-associated vasculitis (granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)) receiving cyclophosphamide (CYC) followed by azathioprine (or mycophenolate mofetil) in the ADVOCATE trial.MethodsKey efficacy outcomes were remission at week 26 and sustained remission at week 52. Additional outcomes included glucocorticoid toxicity, estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR) and safety.ResultsOf 330 patients receiving study medication, 116 (35.2%) received CYC (avacopan group, n=59; prednisone taper group, n=57). Remission at week 26 and sustained remission at week 52 were achieved by 37/59 (62.7%) and 33/59 (55.9%) patients in the avacopan group and 34/57 (59.6%) and 30/57 (52.6%) in the prednisone taper group, respectively. Over 52 weeks, relapses were observed in 13.0% in the avacopan group and 22.6% in the prednisone taper group. Improvement in eGFR, speed of albuminuria reduction and differences in glucocorticoid toxicity favoured the avacopan group. Serious adverse events occurred in 55.9% and 56.1% of patients in the avacopan and prednisone taper groups, respectively.ConclusionsThis subgroup analysis of patients who received CYC shows similar rates of remission in the avacopan and prednisone taper groups. Compared with the prednisone taper regimen, the avacopan regimen was associated with a numerically lower relapse rate, greater improvement in eGFR, faster reduction in UACR, lower glucocorticoid-related toxicity and similar overall safety. These results support the use of avacopan in combination with CYC to treat GPA or MPA.Trial registration numberNCT02994927.