Citations

Abstract Background The prevalence of delirium in intensive care units (ICUs) is high and has a major impact on patient outcomes. Aim To describe delirium assessment instruments, prevalence, interventions and barriers in delirium management in adult and paediatric ICUs; and to explore the association between delirium prevalence and reported interventions and barriers at unit level. Study Design A secondary analysis of the cross‐sectional World Delirium Awareness Day Delirium Survey on 15 March 2023. This was a prospective study to assess the one‐day point delirium prevalence, practices and quality improvement efforts across healthcare systems. Data was analysed descriptively and using multiple linear regression. Results Data of 1612 assessments in 123 ICUs from three German‐speaking countries were analysed. The most frequently used delirium assessment instrument was the Intensive Care Delirium Screening Checklist (43.9%, n = 54). The prevalence of delirium at 8 AM was 18.6% and at 8 PM 20.4% from the 94 ICUs included in the regression analyses. Prevalence for adult and paediatric and mixed ICUs are comparable. Main reported over all unit‐level interventions were ‘pain management’ (95.9%, n = 118), ‘mobilization’ (94.3%, n = 116) and ‘verbal re‐orientation’ (84.6%, n = 104). Main reported over all unit‐level barriers were ‘shortage of staff’ (53.7%, n = 66) and ‘patients who are difficult to assess’ (44.7%, n = 55). Interventions such as ‘avoidance of bladder tubes/catheters’ in all ICUs, ‘use of ear plugs and/or sleep glasses’ in adult ICUs and ‘mobilization’ in paediatric and mixed ICUs were associated with reduced delirium prevalence. Across all ICUs, as well as in both adult and paediatric ICUs, ‘lack of appropriate scores for delirium assessment’ was identified as a significant barrier. Conclusions One fifth of assessed ICU patients suffer from delirium. Several reported unit‐level interventions and barriers may have an impact on delirium prevalence, suggesting an approach for future studies and clinical practice. Relevance to Clinical Practice In clinical practice, unit‐level ‘avoidance of bladder tubes/catheters’, ‘use of ear plugs and/or sleep glasses’ and ‘mobilization’ may be used as delirium prevention and treatment interventions.

Abstract Emphysema’s significant morbidity and mortality underscore the need for reliable outcome metrics in clinical trials. However, commonly accepted chronic obstructive pulmonary disease outcome measures do not adequately capture emphysema severity or progression. Computed tomography (CT) metrics have been validated as accurate indicators of pathological emphysema and predictors of chronic obstructive pulmonary disease progression, exacerbations, and mortality. This position paper reviews the evidence supporting CT densitometry as a biomarker for emphysema, establishes implementation standards, and highlights areas for future research. A systematic literature review addressed three key questions: whether CT densitometry can be used as a diagnostic biomarker of emphysema, whether CT densitometry can be used as a prognostic biomarker, and whether longitudinal change in densitometry can be used as a disease progression monitoring biomarker. Emphysema metrics, such as the percentage of low attenuation areas below −950 Hounsfield units, are validated, highly reproducible diagnostic and prognostic biomarkers. Volume-adjusted lung density is recommended for disease monitoring. Both metrics demonstrate a scan–rescan intraclass correlation coefficient of 0.99 with proper technique. The paper also discusses relevant CT physics, techniques, and sources of variation, including technical factors, physiological changes, and software analysis. Key recommendations for clinical trials include using standardized CT techniques, proper subject selection, and longitudinal evaluation with volume-adjusted lung density.

BACKGROUND: The activation and polarization of T cells play a crucial role in atherosclerosis and dictate athero-inflammation. The epigenetic enzyme EZH2 (enhancer of zeste homolog 2) mediates the H3K27me3 (trimethylation of histone H3 lysine 27) and is pivotal in controlling T cell responses. METHODS: To detail the role of T cell EZH2 in atherosclerosis, we used human carotid endarterectomy specimens to reveal plaque expression and geography of EZH2. Atherosclerosis-prone Apoe (apolipoprotein E)–deficient mice with CD (cluster of differentiation) 4 + or CD8 + T cell–specific Ezh2 deletion (Ezh2 cd4 -knockout [KO], Ezh2 cd8 -KO) were analyzed to unravel the role of T cell Ezh2 in atherosclerosis and T cell–associated immune status. RESULTS: EZH2 expression is elevated in advanced human atherosclerotic plaques and primarily expressed in the T cell nucleus, suggesting the importance of canonical EZH2 function in atherosclerosis. Ezh2 cd4 -KO, but not Ezh2 cd8 -KO, mice showed reduced atherosclerosis with fewer advanced plaques, which contained less collagen and macrophages, indicating that Ezh2 in CD4 + T cells drives atherosclerosis. In-depth analysis of CD4 + T cells of Ezh2 cd4 -KO mice revealed that absence of Ezh2 results in a type 2 immune response with increased Il-4 (interleukin 4) gene and protein expression in the aorta and lymphoid organs. In vitro, Ezh2 -deficient T cells polarized macrophages toward an anti-inflammatory phenotype. Single-cell RNA-sequencing of splenic T cells revealed that Ezh2 deficiency reduced naive, Ccl5 + (C-C motif chemokine ligand 5) and regulatory T cell populations and increased the frequencies of memory T cells and invariant natural killer T (iNKT) cells. Flow cytometric analysis identified a shift toward Th2 (type 2 T helper) effector CD4 + T cells in Ezh2 cd4 -KO mice and confirmed a profound increase in splenic iNKT cells with increased expression of Plzf (promyelocytic leukemia zinc finger), which is the characteristic marker of the iNKT2 subset. Likewise, Zbtb16 ([zinc finger and BTB domain containing 16], the Plzf-encoding gene) transcripts were elevated in the aorta of Ezh2 cd4 -KO mice, suggesting an accumulation of iNKT2 cells in the plaque. H3K27me3–chromatin immunoprecipitation followed by quantitative polymerase chain reaction showed that T cell–Ezh2 regulates the transcription of the Il-4 and Zbtb16 genes. CONCLUSIONS: Our study uncovers the importance of T cell EZH2 in human and mouse atherosclerosis. Inhibition of Ezh2 in CD4 + T cells drives type 2 immune responses, resulting in an accumulation of iNKT2 and Th2 cells, memory T cells and anti-inflammatory macrophages that limit the progression of atherosclerosis.

Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

ABSTRACTThe development of new first‐line treatments for patients with follicular lymphoma (FL) is becoming increasingly challenging due to already excellent survival outcomes. The present study investigated the outcomes of patients with FL who underwent contemporary first‐line therapies but would not have been eligible for inclusion in recent trials and explored how commonly used in/exclusion criteria impacted their survival outcomes. This study included adult patients diagnosed with FL in the period 2000–2018 registered in the Danish Lymphoma Registry. Through searches on ClinicalTrials.gov, four recent 1st line phase 3 randomized controlled trials with R‐Bendamustine, R‐CVP, and/or R‐CHOP as control or experimental arms were included. Inclusion and exclusion criteria for each trial were retrieved and categorized. Patients were then divided into trial‐eligible and ineligible groups according to blood test results correlated to organ function and ECOG performance score (PS). Survival outcomes were significantly worse among trial‐ineligible patients, with adjusted differences between trial‐eligible and ineligible patients of 12%–20% in five‐year overall survival (OS) overall. Inclusion criteria based on PS and renal function were the main drivers of OS differences. More inclusive trials will lead to faster recruitment and secure focus on developing medicines for the group of patients with the worst outcomes.

Importance Vascular injuries require urgent repair to minimize loss of limb and life. Standard revascularization relies on autologous vein or synthetic grafts, but alternative options are needed when adequate vein is not feasible and when clinical conditions preclude safe use of synthetic materials. Objective To evaluate the performance of the acellular tissue engineered vessel (ATEV) in the repair of extremity arterial injuries. Design, Setting, and Participants Two open-label, single-arm, nonrandomized clinical trials, including 1 prospective civilian study (CLN-PRO-V005 [V005]) and 1 retrospective observational study in a war zone (CLN-PRO-V017 [V017]), were conducted from September 2018 to January 2024 (follow-up ongoing) at 19 level 1 trauma centers in the US and Israel and 5 frontline hospitals in Ukraine. Patients had vascular injury, no autologous vein available for emergent revascularization, and risk factors for wound infection. Data include the subset of patients with extremity injuries and were analyzed from September 2023 to January 2024. Intervention The ATEV is a bioengineered vascular conduit grown from human vascular cells, available off the shelf, and implantable without immunosuppression. Main Outcomes and Measures Primary patency at day 30 was the primary outcome. Secondary outcomes included limb salvage, graft infection, and patient survival. A systematic literature review identified synthetic graft benchmarks in the treatment of arterial trauma for the same end points. Results The arterial extremity injury subset included 51 of 69 participants in V005 and 16 of 17 participants in V017. The majority were male (V005, 38 [74.5%]; V017, 16 [100%]), the mean (SD) ages were similar (V005, 33.5 [13.6] years; V017, 34.2 [9.0] years), and the mean (SD) Injury Severity Scores were similar (V005, 20.8 [10.5]; V017, 20.1 [18.9]). Penetrating injuries dominated (V005, 29 patients [56.9%]; V017, 14 patients [87.5%]). At day 30 for the V005 and V017 trials, respectively, ATEV primary patency was 84.3% (95% CI, 72.0%-91.8%) and 93.8% (95% CI, 71.7%-98.9%); secondary patency was 90.2% (95% CI, 79.0%-95.7%) and 93.8% (95% CI, 71.7%-98.9%); amputation rate was 9.8% (95% CI, 4.3%-21.0%) and 0% (95% CI, 0.0%-19.4%); ATEV infection rate was 2.0% (95% CI, 0.4%-10.3%) and 0% (95% CI, 0.0%-19.4%); and death rate was 5.9% (95% CI, 2.0%-15.9%) and 0% (95% CI, 0.0%-19.4%) (no deaths attributed to the ATEV at day 30). Day 30 synthetic graft benchmarks were as follows: secondary patency, 78.9%; amputation, 24.3%; infection, 8.4%; and death, 3.4%. Conclusions and Relevance Results of analysis in the subset of patients with vascular extremity injuries in 2 single-arm trials in civilian and real-world military settings suggest that the ATEV provides benefits in terms of patency, limb salvage, and infection resistance. Comparing ATEV outcomes with synthetic graft benchmarks demonstrated improved outcomes in the treatment of acute vascular injuries of the extremities. The analyses reported herein are limited to the subset of 67 patients with vascular extremity injuries out of 86 patients enrolled in 2 trials and excluded 19 patients with iatrogenic and torso injuries. Had these 19 patients been included in these analyses, the efficacy and safety findings could have been attenuated. Trial Registration ClinicalTrials.gov Identifiers: NCT03005418 , NCT05873959

ABSTRACTBackgroundPediatric organ transplantation is the primary treatment for end‐organ failure. Improving medication adherence and healthcare compliance can decrease healthcare burdens, graft rejection, morbidity, and mortality. Adolescents commonly struggle with non‐adherence, necessitating a smooth transition to adult care. This systematic review aims to assess and evaluate the effectiveness of existing transition tools and models used in the care of pediatric solid organ transplant recipients (pSOTR).MethodsA systematic literature review of studies in electronic databases (PubMed, Google Scholar, and Mendeley) on interventions improving transition in pediatric solid organ transplant recipients (pSOTR) from 2000 to 2022 was conducted. Included studies involved pSOTR before the age of 12 years transitioning to adult care.ResultsA lower proportion of graft acute rejection was observed among pSOTR with more than two transition interventions (10.088%, 95% CI: 0.901%–27.441%, I2 = 85.95%, p < 0.0001, random effects, five studies, n = 155) compared to those with two or fewer interventions (13.892%, 95% CI: 4.588%–27.142%, I2 = 74.73%, p = 0.0014, random effects, six studies, n = 140). Additionally, a significant association was found between transition protocols and lower rejection rates (χ2 = 10.57, p = 0.0011), with multiple protocols showing better outcomes (χ2 = 5.091, p = 0.024). Although adherence scores differed significantly with and without transition protocols (χ2 = 8.75, p = 0.0126), no significant difference was found between single and multiple protocol groups (χ2 = 4.8, p = 0.091).ConclusionThis review identifies various transition models and their impact on adherence and graft rejection, which correlate with morbidity and mortality and influence transplant outcomes. The heterogeneity of data within the current literature necessitates further research to establish causality and develop a standardized transition program aimed at improving patient outcomes.