Predictive Performance of an Updated Polygenic Risk Score for Age-Related Macular Degeneration.

PURPOSE: A recent genome-wide association study of age-related macular degeneration (AMD) identified new AMD-associated risk variants. These variants now can be incorporated into an updated polygenic risk score (PRS). This study aimed to assess the performance of an updated PRS, PRS2023, in an independent cohort of older individuals with retinal imaging data and to compare performance with an older PRS, PRS2016. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 4175 participants of European ancestry, 70 years of age or older, with genotype and retinal imaging data. METHODS: We used logistic regression models and area under the receiver operating characteristic curve (AUC) to assess the performance of PRS2023 compared with PRS2016. AMD status and severity were graded using color fundus photography. MAIN OUTCOME MEASURES: Association of PRS2023 and PRS2016 with AMD risk at baseline. RESULTS: At enrollment among 4175 participants, 2605 participants (62.4%) had no AMD and 853 participants (20.4%), 671 participants (16.1%), and 46 participants (1.1%) had early, intermediate, and late-stage AMD, respectively. More than 27% of the participants with a high PRS2023 (top quartile) had intermediate or late-stage AMD, compared with < 15% for those in the middle 2 quartiles and less than 13% for those in the lowest quartile. Both PRS2023 and PRS2016 were associated significantly with AMD after adjustment for age, sex, smoking status, and lipid levels, with increasing odds ratios (ORs) for worsening AMD grades. PRS2023 outperformed PRS2016 (P = 0.03 for all AMD and P = 0.03 for late AMD, DeLong test comparing AUC). PRS2023 was associated with late-stage AMD with an adjusted OR of 5.05 (95% confidence interval [CI], 3.41-7.47) per standard deviation. The AUC of a model containing conventional or nongenetic risk factors and PRS2023 was 91% (95% CI, 87%-95%) for predicting late-stage AMD, which improved 12% over the model without the PRS (AUC, 79%; P < 0.001 for difference). CONCLUSIONS: A new PRS, PRS2023, for AMD outperforms a previous PRS and predicts increasing risk for late-stage AMD (with stronger association for more severe imaging-confirmed AMD grades). Our findings have clinical implications for the improved prediction and risk stratification of AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Handling missing disease information due to death in diseases that need two visits to diagnose.

In studies that assess disease status periodically, time of disease onset is interval censored between visits. Participants who die between two visits may have unknown disease status after their last visit. In this work, we consider an additional scenario where diagnosis requires two consecutive positive tests, such that disease status can also be unknown at the last visit preceding death. We show that this impacts the choice of censoring time for those who die without an observed disease diagnosis. We investigate two classes of models that quantify the effect of risk factors on disease outcome: a Cox proportional hazards model with death as a competing risk and an illness death model that treats disease as a possible intermediate state. We also consider four censoring strategies: participants without observed disease are censored at death (Cox model only), the last visit, the last visit with a negative test, or the second last visit. We evaluate the performance of model and censoring strategy combinations on simulated data with a binary risk factor and illustrate with a real data application. We find that the illness death model with censoring at the second last visit shows the best performance in all simulation settings. Other combinations show bias that varies in magnitude and direction depending on the differential mortality between diseased and disease-free subjects, the gap between visits, and the choice of the censoring time.

Advancing randomized controlled trial methodologies: The place of innovative trial design in eating disorders research.

Randomized controlled trials can be used to generate evidence on the efficacy and safety of new treatments in eating disorders research. Many of the trials previously conducted in this area have been deemed to be of low quality, in part due to a number of practical constraints. This article provides an overview of established and more innovative clinical trial designs, accompanied by pertinent examples, to highlight how design choices can enhance flexibility and improve efficiency of both resource allocation and participant involvement. Trial designs include individually randomized, cluster randomized, and designs with randomizations at multiple time points and/or addressing several research questions (master protocol studies). Design features include the use of adaptations and considerations for pragmatic or registry-based trials. The appropriate choice of trial design, together with rigorous trial conduct, reporting and analysis, can establish high-quality evidence to advance knowledge in the field. It is anticipated that this article will provide a broad and contemporary introduction to trial designs and will help researchers make informed trial design choices for improved testing of new interventions in eating disorders. PUBLIC SIGNIFICANCE: There is a paucity of high quality randomized controlled trials that have been conducted in eating disorders, highlighting the need to identify where efficiency gains in trial design may be possible to advance the eating disorder research field. We provide an overview of some key trial designs and features which may offer solutions to practical constraints and increase trial efficiency.

Effect of Low-Dose Aspirin Versus Placebo on Incidence of Anemia in the Elderly : A Secondary Analysis of the Aspirin in Reducing Events in the Elderly Trial.

BACKGROUND: Daily low-dose aspirin increases major bleeding; however, few studies have investigated its effect on iron deficiency and anemia. OBJECTIVE: To investigate the effect of low-dose aspirin on incident anemia, hemoglobin, and serum ferritin concentrations. DESIGN: Post hoc analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial. (ClinicalTrials.gov: NCT01038583). SETTING: Primary/community care in Australia and the United States. PARTICIPANTS: Community-dwelling persons aged 70 years or older (≥65 years for Black persons and Hispanic persons). INTERVENTION: 100 mg of aspirin daily or placebo. MEASUREMENTS: Hemoglobin concentration was measured annually in all participants. Ferritin was measured at baseline and 3 years after random assignment in a large subset. RESULTS: 19 114 persons were randomly assigned. Anemia incidence in the aspirin and placebo groups was 51.2 events and 42.9 events per 1000 person-years, respectively (hazard ratio, 1.20 [95% CI, 1.12 to 1.29]). Hemoglobin concentrations declined by 3.6 g/L per 5 years in the placebo group and the aspirin group experienced a steeper decline by 0.6 g/L per 5 years (CI, 0.3 to 1.0 g/L). In 7139 participants with ferritin measures at baseline and year 3, the aspirin group had greater prevalence than placebo of ferritin levels less than 45 µg/L at year 3 (465 [13%] vs. 350 [9.8%]) and greater overall decline in ferritin by 11.5% (CI, 9.3% to 13.7%) compared with placebo. A sensitivity analysis quantifying the effect of aspirin in the absence of major bleeding produced similar results. LIMITATIONS: Hemoglobin was measured annually. No data were available on causes of anemia. CONCLUSION: Low-dose aspirin increased incident anemia and decline in ferritin in otherwise healthy older adults, independent of major bleeding. Periodic monitoring of hemoglobin should be considered in older persons on aspirin. PRIMARY FUNDING SOURCE: National Institutes of Health and Australian National Health and Medical Research Council.

Orange G degradation by heterogeneous peroxymonosulfate activation based on magnetic MnFe2O4/α-MnO2 hybrid.

Wastewater containing an azo dye Orange G (OG) causes massive environmental pollution, thus it is critical to develop a highly effective, environmental-friendly, and reusable catalyst in peroxymonosulfate (PMS) activation for OG degradation. In this work, we successfully applied a magnetic MnFe2O4/α-MnO2 hybrid fabricated by a simple hydrothermal method for OG removal in water. The characteristics of the hybrid were investigated by X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller method, vibrating sample magnetometry, electron paramagnetic resonance, thermogravimetric analysis, and X-ray photoelectron spectroscopy. The effects of operational parameters (i.e., catalytic system, catalytic dose, solution pH, and temperature) were investigated. The results exhibited that 96.8% of OG degradation was obtained with MnFe2O4/α-MnO2(1:9)/PMS system in 30 min regardless of solution pH changes. Furthermore, the possible reaction mechanism of the coupling system was proposed, and the degradation intermediates of OG were identified by mass spectroscopy. The radical quenching experiments and EPR tests demonstrated that SO4•̶, O2•̶, and 1O2 were the primary reactive oxygen species responsible for the OG degradation. The hybrid also displayed unusual stability with less than 30% loss in the OG removal after four sequential cycles. Overall, magnetic MnFe2O4/α-MnO2 hybrid could be used as a high potential activator of PMS to remove orange G and maybe other dyes from wastewater.

Dynamic Prediction of Death in Patients With Tuberculous Meningitis Using Time-updated Glasgow Coma Scale and Plasma Sodium Measurements.

BACKGROUND: Pretreatment predictors of death from tuberculous meningitis (TBM) are well established, but whether outcome can be predicted more accurately after the start of treatment by updated clinical variables is unknown. Hence, we developed and validated models that dynamically predict mortality using time-updated Glasgow Coma Scale (GCS) and plasma sodium measurements, together with patient baseline characteristics. METHODS: We included 1048 adults from 4 TBM studies conducted in southern Vietnam from 2004 to 2016. We used a landmarking approach to predict death within 120 days after treatment initiation using time-updated data during the first 30 days of treatment. Separate models were built for patients with and without human immunodeficiency virus (HIV) infection. We used the area under the receiver operating characteristic curve (AUC) to evaluate performance of the models at days 10, 20, and 30 of treatment to predict mortality by 60, 90, and 120 days. Our internal validation was corrected for overoptimism using bootstrap. We provide a web-based application that computes mortality risk within 120 days. RESULTS: Higher GCS indicated better prognosis in all patients. In HIV-infected patients, higher plasma sodium was uniformly associated with good prognosis, whereas in HIV-uninfected patients the association was heterogeneous over time. The bias-corrected AUC of the models ranged from 0.82 to 0.92 and 0.81 to 0.85 in HIV-uninfected and HIV-infected individuals, respectively. The models outperformed the previously published baseline models. CONCLUSIONS: Time-updated GCS and plasma sodium measurements improved predictions based solely on information obtained at diagnosis. Our models may be used in practice to define those with poor prognosis during treatment.

A comparison of model selection methods for prediction in the presence of multiply imputed data.

Many approaches for variable selection with multiply imputed data in the development of a prognostic model have been proposed. However, no method prevails as uniformly best. We conducted a simulation study with a binary outcome and a logistic regression model to compare two classes of variable selection methods in the presence of MI data: (I) Model selection on bootstrap data, using backward elimination based on AIC or lasso, and fit the final model based on the most frequently (e.g. ≥50% ) selected variables over all MI and bootstrap data sets; (II) Model selection on original MI data, using lasso. The final model is obtained by (i) averaging estimates of variables that were selected in any MI data set or (ii) in 50% of the MI data; (iii) performing lasso on the stacked MI data, and (iv) as in (iii) but using individual weights as determined by the fraction of missingness. In all lasso models, we used both the optimal penalty and the 1-se rule. We considered recalibrating models to correct for overshrinkage due to the suboptimal penalty by refitting the linear predictor or all individual variables. We applied the methods on a real dataset of 951 adult patients with tuberculous meningitis to predict mortality within nine months. Overall, applying lasso selection with the 1-se penalty shows the best performance, both in approach I and II. Stacking MI data is an attractive approach because it does not require choosing a selection threshold when combining results from separate MI data sets.

Prognostic Models for 9-Month Mortality in Tuberculous Meningitis.

Background: Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. We developed and validated prognostic models for 9-month mortality in adults with TBM, with or without human immunodeficiency virus (HIV) infection. Methods: We included 1699 subjects from 4 randomized clinical trials and 1 prospective observational study conducted at 2 major referral hospitals in Southern Vietnam from 2001-2015. Modeling was based on multivariable Cox proportional hazards regression. The final prognostic models were validated internally and temporally and were displayed using nomograms and a Web-based app (https://thaole.shinyapps.io/tbmapp/). Results: 951 HIV-uninfected and 748 HIV-infected subjects with TBM were included; 219 of 951 (23.0%) and 384 of 748 (51.3%) died during 9-month follow-up. Common predictors for increased mortality in both populations were higher Medical Research Council (MRC) disease severity grade and lower cerebrospinal fluid lymphocyte cell count. In HIV-uninfected subjects, older age, previous tuberculosis, not receiving adjunctive dexamethasone, and focal neurological signs were additional risk factors; in HIV-infected subjects, lower weight, lower peripheral blood CD4 cell count, and abnormal plasma sodium were additional risk factors. The areas under the receiver operating characteristic curves (AUCs) for the final prognostic models were 0.77 (HIV-uninfected population) and 0.78 (HIV-infected population), demonstrating better discrimination than the MRC grade (AUC, 0.66 and 0.70) or Glasgow Coma Scale score (AUC, 0.68 and 0.71) alone. Conclusions: The developed models showed good performance and could be used in clinical practice to assist physicians in identifying patients with TBM at high risk of death and with increased need of supportive care.

Homology differences between complete Sacbrood virus genomes from infected Apis mellifera and Apis cerana honeybees in Korea.

Sacbrood virus (SBV) represents a serious threat to the health of managed honeybees. We determined four complete SBV genomic sequences (AmSBV-Kor1, AmSBV-Kor2, AcSBV-Kor3, and AcSBV-Kor4) isolated from Apis mellifera and Apis cerana in various regions of South Korea. A phylogenetic tree was constructed from the complete genomic sequences of these Korean SBVs (KSBVs) and 21 previously reported SBV sequences from other countries. Three KSBVs (not AmSBV-Kor1) clustered with previously reported Korean genomes, but separately from SBV genomes from other countries. The KSBVs shared 90-98 % identity, and 89-97 % identity with the genomes from other countries. AmSBV-Kor1 was least similar (~90 % identity) to the other KSBVs, and was most similar to previously reported strains AmSBV-Kor21 (97 %) and AmSBV-UK (93 %). Phylogenetic analysis of the partial VP1 region sequences indicated that SBVs clustered by host species and country of origin. The KSBVs were aligned with nine previously reported complete SBV genomes and compared. The KSBVs were most different from the other genomes at the end of the 5' untranslated region and in the entire open reading frame. A SimPlot graph of the VP1 region confirmed its high variability, especially between the SBVs infecting A. mellifera and A. cerana. In this genomic region, SBVs from A. mellifera species contain an extra continuous 51-nucleotide sequence relative to the SBVs from A. cerana. This genomic diversity may reflect the adaptation of SBV to specific hosts, viral cross-infections, and the spatial distances separating the KSBVs from other SBVs.

Analysis of the RdRp, intergenic and structural polyprotein regions, and the complete genome sequence of Kashmir bee virus from infected honeybees (Apis mellifera) in Korea.

Kashmir bee virus (KBV) is one of the most common viral infections in honeybees. In this study, a phylogenetic analysis was performed using nine partial nucleotide sequences of RdRp and the structural polyprotein regions of South Korean KBV genotypes, as well as nine previously reported KBV genotypes from various countries and two closely related genotypes of Israeli acute paralysis virus (IAPV) and Acute bee paralysis virus (ABPV). The Korean KBV genotypes were highly conserved with 94-99 % shared identity, but they also shared 88-95 % identity with genotypes from various countries, and they formed a separate KBV cluster in the phylogenetic tree. The complete genome sequence of Korean KBV was also determined and aligned with previously reported complete reference genome sequences of KBV, IAPV, and ABPV to compare different genomic regions. The complete Korean KBV genome shared 93, 79, and 71 % similarity with the complete reference genomes of KBV, IAPV, and ABPV, respectively. The Korean KBV was highly conserved relative to the reference KBV genomes in the intergenic and 3' untranslated region (UTR), but it had a highly variable 5' UTR, whereas there was little divergence in the helicase and 3C-protease of the nonstructural protein, and the external domains of the structural polyprotein region. Thus, genetic recombination and geographical distance may explain the genomic variations between the Korean and reference KBV genotypes.

Clonal hematopoiesis of indeterminate potential as a prognostic factor: a systematic review and meta-analysis.

ABSTRACT: With advances in sequencing, individuals with clonal hematopoiesis of indeterminate potential (CHIP) are increasingly being identified, making it essential to understand its prognostic implications. We conducted a systematic review of studies comparing the risk of clinical outcomes in individuals with and without CHIP. We searched MEDLINE and EMBASE and included original research reporting an outcome risk measure in individuals with CHIP, adjusted for the effect of age. From the 3305 studies screened, we included 88 studies with 45 to 470 960 participants. Most studies had a low-to-moderate risk of bias in all domains of the Quality in Prognostic Factor Studies tool. Random-effects meta-analyses were performed for outcomes reported in at least 3 studies. CHIP conferred an increased risk of all-cause mortality (hazard ratio [HR], 1.34; 95% confidence interval, 1.19-1.50), cancer mortality (HR, 1.46; 1.13-1.88), composite cardiovascular events (HR, 1.40; 1.19-1.65), coronary heart disease (HR, 1.76; 1.27-2.44), stroke (HR, 1.16; 1.05-1.28), heart failure (HR, 1.27; 1.15-1.41), hematologic malignancy (HR, 4.28; 2.29-7.98), lung cancer (HR, 1.40; 1.27-1.54), renal impairment (HR, 1.25; 1.18-1.33) and severe COVID-19 (odds ratio [OR], 1.46; 1.18-1.80). CHIP was not associated with cardiovascular mortality (HR, 1.09; 0.97-1.22), except in the subgroup analysis restricted to larger clones (HR, 1.31; 1.12-1.54). Isolated DNMT3A mutations did not increase the risk of myeloid malignancy, all-cause mortality, or renal impairment. The reasons for heterogeneity between studies included differences in definitions and measurements of CHIP and the outcomes, and populations studied. In summary, CHIP is associated with diverse clinical outcomes, with clone size, specific gene, and inherent patient characteristics important mediators of risk.

Immunoglobulin replacement vs prophylactic antibiotics for hypogammaglobulinemia secondary to hematological malignancy.

ABSTRACT: Immunoglobulin replacement and prophylactic antibiotics are commonly used to prevent infections in patients with secondary hypogammaglobulinemia due to hematological malignancies but have never been directly compared. In this randomized controlled feasibility trial conducted in 7 hospitals in Australia and New Zealand, we enrolled patients with secondary hypogammaglobulinemia with either a history of recurrent/severe infection or an immunoglobulin G level <4 g/L. Participants were randomized in a 1:2 ratio to immunoglobulin (0.4 g/kg per 4 weeks IV) or daily antibiotics (trimethoprim-sulfamethoxazole 160 mg/800 mg or, if contraindicated, 100 mg doxycycline) for 12 months. Participants allocated to antibiotics were allowed to crossover after grade ≥3 infections. The primary outcome was proportion of patients alive on the assigned treatment 12 months after randomization. Between August 2017 and April 2019, 63 patients were randomized: 42 to antibiotics and 21 to immunoglobulin. Proportion of participants alive on allocated treatment at 12 months was 76% in the immunoglobulin and 71% in the antibiotic arm (Fisher exact test P=.77; odds ratio, 0.78; 95% CI, 0.22-2.52). The lower quartile for time to first major infection (median, not reached) was 11.1 months for the immunoglobulin and 9.7 months for the antibiotic arm (log-rank test, P=.65). Three participants in the immunoglobulin and 2 in the antibiotic arm had grade ≥3 treatment-related adverse events. A similar proportion of participants remained on antibiotic prophylaxis at 12 months to those on immunoglobulin, with similar rates of major infections. Our findings support the feasibility of progressing to a phase 3 trial. Trial registration #ACTRN12616001723471.

Effect of Low-Dose Aspirin on the Course of Age-Related Macular Degeneration: A Secondary Analysis of the ASPREE Randomized Clinical Trial.

Importance: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in old age. There is no proven intervention to prevent AMD and, apart from lifestyle, nutritional, and supplement advice, there is no intervention to delay its progression. Objective: To determine the impact of long-term low-dose aspirin on the incidence and progression of AMD. Design, Setting and Participants: The Aspirin in Reducing Events in the Elderly-AMD (ASPREE-AMD) study was an Australian-based substudy of the ASPREE trial, a multicenter, international, randomized, double-masked, placebo-clinical trial investigating the efficacy of low-dose aspirin in prolonging disability-free survival among older individuals. Retinal photography was conducted at baseline from March 2010 to January 2015, then 3 and 5 years after randomization. AMD status was determined using color retinal images and treatment records. Australian participants in ASPREE aged 70 years and older without dementia, independence-limiting physical disability, cardiovascular disease, or chronic illness limiting 5-year survival and with gradable retinal images at baseline were included. Data were analyzed from December 2022 to December 2023. Interventions: Aspirin (100 mg daily, enteric coated) or placebo. Main Outcomes and Measures: Incidence of AMD and progression from early/intermediate to late AMD. Outcomes were analyzed by modified intention-to-treat analysis. Results: A total of 4993 participants were enrolled in this substudy. Baseline characteristics were similar between groups. At the time of sponsor-determined trial termination, retinal follow-up data were available for 3208 participants, 3171 of whom were analyzed for AMD incidence and progression, with a median (IQR) age of 73.5 (71.5-76.4) years and even sex distribution (1619 [51%] female). Median (IQR) follow-up time was 3.1 (3.0-3.5) years. Cumulative AMD incidence was 195 of 1004 (19.4%) in the aspirin group and 187 of 979 (19.1%) in the placebo group (relative risk [RR], 1.02; 95% CI, 0.85-1.22; P = .86). Cumulative progression from early/intermediate AMD to late AMD was observed in 14 of 615 (2.3%) participants in the aspirin group and 18 of 573 (3.1%) in the placebo group (RR, 0.72; 95% CI, 0.36-1.44; P = .36). Conclusions and Relevance: In this trial, low-dose aspirin administered for 3 years did not affect the incidence of AMD. The evidence was weaker for progression of AMD due to low number of progressed cases. Overall, these results do not support suggestion that low-dose daily aspirin prevents the development or progression of AMD. Trial Registration: anzctr.org Identifier: ACTRN12613000755730.

Increased frequencies of CD4+ CD25(high) regulatory T cells in acute dengue infection.

Dengue virus infection is an increasingly important tropical disease, causing 100 million cases each year. Symptoms range from mild febrile illness to severe hemorrhagic fever. The pathogenesis is incompletely understood, but immunopathology is thought to play a part, with antibody-dependent enhancement and massive immune activation of T cells and monocytes/macrophages leading to a disproportionate production of proinflammatory cytokines. We sought to investigate whether a defective population of regulatory T cells (T reg cells) could be contributing to immunopathology in severe dengue disease. CD4(+)CD25(high)FoxP3(+) T reg cells of patients with acute dengue infection of different severities showed a conventional phenotype. Unexpectedly, their capacity to suppress T cell proliferation and to secrete interleukin-10 was not altered. Moreover, T reg cells suppressed the production of vasoactive cytokines after dengue-specific stimulation. Furthermore, T reg cell frequencies and also T reg cell/effector T cell ratios were increased in patients with acute infection. A strong indication that a relative rise of T reg cell/effector T cell ratios is beneficial for disease outcome comes from patients with mild disease in which this ratio is significantly increased (P < 0.0001) in contrast to severe cases (P = 0.2145). We conclude that although T reg cells expand and function normally in acute dengue infection, their relative frequencies are insufficient to control the immunopathology of severe disease.

Plant-Associated Representatives of the Bacillus cereus Group Are a Rich Source of Antimicrobial Compounds.

Seventeen bacterial strains able to suppress plant pathogens have been isolated from healthy Vietnamese crop plants and taxonomically assigned as members of the Bacillus cereus group. In order to prove their potential as biocontrol agents, we perform a comprehensive analysis that included the whole-genome sequencing of selected strains and the mining for genes and gene clusters involved in the synthesis of endo- and exotoxins and secondary metabolites, such as antimicrobial peptides (AMPs). Kurstakin, thumolycin, and other AMPs were detected and characterized by different mass spectrometric methods, such as MALDI-TOF-MS and LIFT-MALDI-TOF/TOF fragment analysis. Based on their whole-genome sequences, the plant-associated isolates were assigned to the following species and subspecies: B. cereus subsp. cereus (6), B. cereus subsp. bombysepticus (5), Bacillus tropicus (2), and Bacillus pacificus. These three isolates represent novel genomospecies. Genes encoding entomopathogenic crystal and vegetative proteins were detected in B. cereus subsp. bombysepticus TK1. The in vitro assays revealed that many plant-associated isolates enhanced plant growth and suppressed plant pathogens. Our findings indicate that the plant-associated representatives of the B. cereus group are a rich source of putative antimicrobial compounds with potential in sustainable agriculture. However, the presence of virulence genes might restrict their application as biologicals in agriculture.

Transfusion practices in intensive care units: An Australian and New Zealand point prevalence study.

Objective: To describe current transfusion practices in intensive care units (ICUs) in Australia and New Zealand, compare them against national guidelines, and describe how viscoelastic haemostatic assays (VHAs) are used in guiding transfusion decisions. Design setting and participants: Prospective, multicentre, binational point-prevalence study. All adult patients admitted to participating ICUs on a single day in 2021. Main outcome measures: Transfusion types, amounts, clinical reasons, and triggers; use of anti-platelet medications, anti-coagulation, and VHA. Results: Of 712 adult patients in 51 ICUs, 71 (10%) patients received a transfusion during the 24hr period of observation. Compared to patients not transfused, these patients had higher Acute Physiology and Chronic Health Evaluation II scores (19 versus 17, p = 0.02), a greater proportion were mechanically ventilated (49.3% versus 37.3%, p < 0.05), and more had systemic inflammatory response syndrome (70.4% versus 51.3%, p < 0.01). Overall, 63 (8.8%) patients received red blood cell (RBC) transfusions, 10 (1.4%) patients received platelet transfusions, 6 (0.8%) patients received fresh frozen plasma (FFP), and 5 (0.7%) patients received cryoprecipitate. VHA was available in 42 (82.4%) sites but only used in 6.6% of transfusion episodes when available. Alignment with guidelines was found for 98.6% of RBC transfusions, but only 61.6% for platelet, 28.6% for FFP, and 20% for cryoprecipitate transfusions. Conclusions: Non-RBC transfusion decisions are often not aligned with guidelines and VHA is commonly available but rarely used to guide transfusions. Better evidence to guide transfusions in ICUs is needed.

Low-Dose Aspirin and the Risk of Stroke and Intracerebral Bleeding in Healthy Older People: Secondary Analysis of a Randomized Clinical Trial.

Importance: Low-dose aspirin has been widely used for primary and secondary prevention of stroke. The balance between potential reduction of ischemic stroke events and increased intracranial bleeding has not been established in older individuals. Objective: To establish the risks of ischemic stroke and intracranial bleeding among healthy older people receiving daily low-dose aspirin. Design, Setting, and Participants: This secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, double-blind, placebo-controlled trial of daily low-dose aspirin was conducted among community-dwelling people living in Australia or the US. Participants were older adults free of symptomatic cardiovascular disease. Recruitment took place between 2010 and 2014, and participants were followed up for a median (IQR) of 4.7 (3.6-5.7) years. This analysis was completed from August 2021 to March 2023. Interventions: Daily 100-mg enteric-coated aspirin or matching placebo. Main Outcomes and Measures: Stroke and stroke etiology were predetermined secondary outcomes and are presented with a focus on prevention of initial stroke or intracranial bleeding event. Outcomes were assessed by review of medical records. Results: Among 19 114 older adults (10 782 females [56.4%]; median [IQR] age, 74 [71.6-77.7] years), 9525 individuals received aspirin and 9589 individuals received placebo. Aspirin did not produce a statistically significant reduction in the incidence of ischemic stroke (hazard ratio [HR], 0.89; 95% CI, 0.71-1.11). However, a statistically significant increase in intracranial bleeding was observed among individuals assigned to aspirin (108 individuals [1.1%]) compared with those receiving placebo (79 individuals [0.8%]; HR, 1.38; 95% CI, 1.03-1.84). This occurred by an increase in a combination of subdural, extradural, and subarachnoid bleeding with aspirin compared with placebo (59 individuals [0.6%] vs 41 individuals [0.4%]; HR, 1.45; 95% CI, 0.98-2.16). Hemorrhagic stroke was recorded in 49 individuals (0.5%) assigned to aspirin compared with 37 individuals (0.4%) in the placebo group (HR, 1.33; 95% CI, 0.87-2.04). Conclusions and Relevance: This study found a significant increase in intracranial bleeding with daily low-dose aspirin but no significant reduction of ischemic stroke. These findings may have particular relevance to older individuals prone to developing intracranial bleeding after head trauma. Trial Registration: ISRCTN.org Identifier: ISRCTN83772183.

Genome-Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene.

Background The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent ASCVD carry cardioprotective genetic variants that contribute to ASCVD resilience. Methods and Results We performed a genome-wide association study using a 10-year predicted ASCVD risk score as a quantitative trait, calculated only in asymptomatic older individuals aged ≥70 years without prevalent ASCVD. Our discovery genome-wide association study of N=12 031 ASCVD event-free individuals from the ASPREE (Aspirin in Reducing Events in the Elderly) trial identified 2 independent variants, rs9939224 (P<5×10-8) and rs56156922 (P<10-6), in the CETP (cholesteryl ester transfer protein) gene. The CETP gene is a regulator of plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and lipoprotein(a) levels, and it is a therapeutic drug target. The associations were replicated in the UK Biobank (subpopulation of N=13 888 individuals aged ≥69 years without prevalent ASCVD). Carriers of the identified CETP variants (versus noncarriers) had higher plasma high-density lipoprotein cholesterol levels, lower plasma low-density lipoprotein cholesterol levels, and reduced risk of incident ASCVD events during follow-up. Expression quantitative trait loci analysis predicted the identified CETP variants reduce CETP gene expression across various tissues. Previously reported associations between genetic CETP inhibition and increased risk of age-related macular degeneration were not observed among the 3917 ASPREE trial participants with retinal imaging and genetic data available. Conclusions Common genetic variants in the CETP gene region are associated with cardiovascular resilience during aging. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.