Critical care syndromes such as sepsis, acute respiratory distress syndrome (ARDS) and trauma continue to have unacceptably high morbidity and mortality, with progress limited by the inherent heterogeneity within syndromic illnesses. Although numerous immune endotypes have been proposed for sepsis and critical care, the similarities and differences between these endotypes remain unclear, hindering clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine in critical care through the sharing of transcriptomic data. Here, evaluating the overlap of existing immune endotypes in sepsis across >7,074 samples from 37 independent cohorts, we developed cell-type-specific gene expression signatures to quantify dysregulation within immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. Importantly, this dysregulation was also observed in patients with ARDS, trauma and burns, suggesting a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation are associated with differential mortality in patients treated with anakinra in the SAVE-MORE trial (n = 452) and corticosteroids in the VICTAS (n = 89) and VANISH (n = 117) trials, underscoring their prognostic and therapeutic implications. In conclusion, our proposed immunology-based framework for quantifying cellular compartment dysregulation offers a potentially valuable tool for understanding immune dysregulation in critical illness with prognostic and therapeutic significance.

Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1β, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis.

Background: Early sepsis diagnosis is essential to allow timely initiation of adequate care. The TriVerity™ Test, performed on the Myrna™ Instrument, is the first rapid high-multiplex host-response mRNA diagnostic test that supports clinical decision-making by evaluating the likelihood of bacterial and/or viral infections and severity of illness. We present findings of the first, proof of concept, real-world evaluation in an emergency department (ED). Methods: Blood was collected in PAXgene^® Blood RNA tubes from adult patients visiting the ED with suspicion of infection between 4th December 2023 and 22nd January 2024. TriVerity was performed within 1 h (RNA extraction and amplification of 29 host mRNAs using LAMP technology on the Myrna Instrument within approximately 30 min). TriVerity generates three diagnostic scores (likelihood of bacterial infection, viral infection, and illness severity), each classified into five discrete interpretation bands (very low, low, moderate, high, and very high). Post hoc chart reviews were performed after hospital discharge to clinically adjudicate the infection status (consensus and forced adjudication). Results: Among 60 patients, there were 20 (33%) bacterial infections, 15 (25%) viral infections, 11 (18%) bacterial–viral coinfections and 14 (23%) did not have an infection under forced adjudication. Under consensus adjudication, bacterial results demonstrated 95% rule-in specificity and 95% rule-out sensitivity. Viral results demonstrated rule-in specificity 100% and 92% rule-out sensitivity. Since only three patients were admitted to the ICU or died in this cohort, we cannot draw firm conclusions about the predictive value of the test for severe endpoints. Conclusions: TriVerity is a rapid whole-blood host-response test to reliably detect the presence or absence of bacterial and/or viral infections, as well as to assess illness severity in patients presenting to the ED. Its quick turnaround time aligns with the ED workflow, offering timely insights for clinical decision-making. Results from upcoming large-scale validation studies will provide more detailed results on the diagnostic and prognostic accuracy of the test.

Protein-bound uremic toxins (PBUTs) are associated with the progression of chronic kidney disease (CKD) and its associated morbidity and mortality. The conventional dialysis techniques are unable to efficiently remove PBUTs due to their plasma protein binding. Therefore, novel approaches are being developed, but these require validation in animals before clinical trials can begin. We conducted a systematic review to document PBUT concentrations in various models and species. The search strategy returned 1163 results for which abstracts were screened, resulting in 65 full-text papers for data extraction (rats (n = 41), mice (n = 17), dogs (n = 3), cats (n = 4), goats (n = 1), and pigs (n = 1)). We performed descriptive and comparative analyses on indoxyl sulfate (IS) concentrations in rats and mice. The data on large animals and on other PBUTs were too heterogeneous for pooled analysis. Most rodent studies reported mean uremic concentrations of plasma IS close to or within the range of those during kidney failure in humans, with the highest in tubular injury models in rats. Compared to nephron loss models in rats, a greater rise in plasma IS compared to creatinine was found in tubular injury models, suggesting tubular secretion was more affected than glomerular filtration. In summary, tubular injury rat models may be most relevant for the in vivo validation of novel PBUT-lowering strategies for kidney failure in humans.

Early sepsis recognition is challenging due to its heterogeneous presentations and limited rapid diagnostic and prognostic tools. The TriVerity ^TM Test, a high-multiplex host-response mRNA point-of-care test, supports clinical decision-making by estimating infection likelihood and illness severity. This study assesses TriVerity’s accuracy in Dutch emergency department (ED) patients. Adult ED patients with suspected infection and Systemic Inflammatory Response Syndrome score (SIRS) ≥2 or quick Sequential Organ Failure Assessment (qSOFA) ≥2 were prospectively included by the Acutelines data/biobank. The TriVerity test provides three scores: likelihood of bacterial infection, viral infection, and illness severity. Infection status was determined post hoc by independent physicians through clinical consensus and forced adjudication. Illness severity was defined as ICU admission or death within 7 days after ED admission. Among the 467 patients included, 234 (50%) had a bacterial infection, 80 (17%) had a viral infection, 86 (18%) had a bacterial–viral co-infection, and 67 (14%) had no infection. For bacterial infections, the TriVerity assay demonstrated a rule-in specificity of 89–94% and a rule-out sensitivity of 87–92%, depending on the adjudication method (forced vs. consensus). For viral infections, the rule-in specificity was 92–95%, and the rule-out sensitivity ranged from 76 to 92%. The illness severity score showed a rule-in specificity of 83–86% and a rule-out sensitivity of 85–87%. The TriVerity test demonstrated high specificity and sensitivity for both bacterial and viral infections, with high sensitivity and modest positive predictive value in identifying patients at risk of developing severe illness.